Challenges and limitations of the therapeutic application of protein kinase inhibitors
Aspect
Neurodegenerative disorders
Psychiatric disorders
Disease complexity
- Heterogeneity of neurodegenerative diseases (e.g., sporadic vs familial forms). - Multiple pathways contribute to disease progression, requiring combination therapies.
- Psychiatric disorders have highly complex and poorly defined molecular underpinnings. - Symptoms and etiologies overlap among disorders (e.g., bipolar disorder, schizophrenia, depression).
Blood-brain barrier (BBB)
- PKIs must effectively cross the BBB, which limits many candidate drugs. - Chronic neurodegenerative diseases require sustained drug delivery, raising concerns about toxicity and drug stability.
- PKIs face similar BBB challenges but are typically needed for short to intermediate-term treatments, unlike the chronic therapies required for neurodegeneration.
Off-target effects
- Kinases are involved in numerous signaling pathways, leading to potential toxicity from off-target inhibition (e.g., cardiovascular, immune effects).
- Psychiatric patients may be more susceptible to side effects such as mood instability or cognitive impairment due to off-target effects.
Patient-specific variability
- Genetic mutations (e.g., LRRK2 in Parkinson’s) exist in a subset of patients, complicating treatment generalizability.
- Lack of reliable biomarkers hampers patient stratification and target validation for kinase inhibitors.
Long-term safety
- Long treatment durations required for neurodegeneration amplify safety concerns (e.g., hepatotoxicity, immune suppression).
- Long-term safety studies are needed, especially for disorders requiring continuous maintenance therapy (e.g., bipolar disorder).
PKIs: protein kinase inhibitors; LRRK2: leucine-rich repeat kinase 2
Declarations
Author contributions
AARV and PB: Investigation, Writing—original draft. IM: Writing—review & editing, Supervision. All authors read and approved the submitted version.
Conflicts of interest
The authors declare that they have no conflicts of interest.
Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.
References
Berndt N, Karim RM, Schönbrunn E. Advances of small molecule targeting of kinases.Curr Opin Chem Biol. 2017;39:126–32. [DOI] [PubMed] [PMC]
Vlastaridis P, Kyriakidou P, Chaliotis A, Peer YVd, Oliver SG, Amoutzias GD. Estimating the total number of phosphoproteins and phosphorylation sites in eukaryotic proteomes.Gigascience. 2017;6:1–11. [DOI] [PubMed] [PMC]
Kawahata I, Fukunaga K. Protein Kinases and Neurodegenerative Diseases.Int J Mol Sci. 2023;24:5574. [DOI] [PubMed] [PMC]
Chong ZZ, Shang YC, Wang S, Maiese K. A Critical Kinase Cascade In Neurological Disorders: Pi3K, Akt and Mtor.Future Neurol. 2012;7:733–48. [DOI] [PubMed] [PMC]
Baltussen LL, Rosianu F, Ultanir SK. Kinases in synaptic development and neurological diseases.Prog Neuropsychopharmacol Biol Psychiatry. 2018;84:343–52. [DOI] [PubMed]
Lee PY, Yeoh Y, Low TY. A recent update on small-molecule kinase inhibitors for targeted cancer therapy and their therapeutic insights from mass spectrometry-based proteomic analysis.FEBS J. 2023;290:2845–64. [DOI] [PubMed]
Jr RR. Properties of FDA-approved small molecule protein kinase inhibitors: A 2024 update.Pharmacol Res. 2024;200:107059. [DOI] [PubMed]
Chico LK, Eldik LJV, Watterson DM. Targeting protein kinases in central nervous system disorders.Nat Rev Drug Discov. 2009;8:892–909. [DOI] [PubMed] [PMC]
Lui A, Vanleuven J, Perekopskiy D, Liu D, Xu D, Alzayat O, et al. FDA-Approved Kinase Inhibitors in Preclinical and Clinical Trials for Neurological Disorders.Pharmaceuticals (Basel). 2022;15:1546. [DOI] [PubMed] [PMC]
Araujo J, Logothetis C. Dasatinib: a potent SRC inhibitor in clinical development for the treatment of solid tumors.Cancer Treat Rev. 2010;36:492–500. [DOI] [PubMed] [PMC]
Tevaarwerk AJ, Kolesar JM. Lapatinib: a small-molecule inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor-2 tyrosine kinases used in the treatment of breast cancer.Clin Ther. 2009;31 Pt 2:2332–48. [DOI] [PubMed]
Joensuu H, Dimitrijevic S. Tyrosine kinase inhibitor imatinib (STIS71) as an anticancer agent for solid tumours.Ann Med. 2001;33:451–5. [DOI] [PubMed]
Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling.Mol Cancer Ther. 2008;7:3129–40. [DOI] [PubMed]
Lugowska I, Koseła-Paterczyk H, Kozak K, Rutkowski P. Trametinib: a MEK inhibitor for management of metastatic melanoma.Onco Targets Ther. 2015;8:2251–9. [DOI] [PubMed] [PMC]
Lan A, Chen J, Zhao Y, Chai Z, Hu Y. mTOR Signaling in Parkinson’s Disease.Neuromolecular Med. 2017;19:1–10. [DOI] [PubMed]
French JA, Lawson JA, Yapici Z, Ikeda H, Polster T, Nabbout R, et al. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study.Lancet. 2016;388:2153–63. [DOI] [PubMed]
Franz DN, Lawson JA, Yapici Z, Ikeda H, Polster T, Nabbout R, et al. Everolimus for treatment-refractory seizures in TSC: Extension of a randomized controlled trial.Neurol Clin Pract. 2018;8:412–20. [DOI] [PubMed] [PMC]
Johnson TK, Soellner MB. Bivalent Inhibitors of c-Src Tyrosine Kinase That Bind a Regulatory Domain.Bioconjug Chem. 2016;27:1745–9. [DOI] [PubMed] [PMC]
Nelson V, Ziehr J, Agulnik M, Johnson M. Afatinib: emerging next-generation tyrosine kinase inhibitor for NSCLC.Onco Targets Ther. 2013;6:135–43. [DOI] [PubMed] [PMC]
Tiwari SR, Mishra P, Abraham J. Neratinib, A Novel HER2-Targeted Tyrosine Kinase Inhibitor.Clin Breast Cancer. 2016;16:344–8. [DOI] [PubMed]
Herbert C, Schieborr U, Saxena K, Juraszek J, Smet FD, Alcouffe C, et al. Molecular mechanism of SSR128129E, an extracellularly acting, small-molecule, allosteric inhibitor of FGF receptor signaling.Cancer Cell. 2013;23:489–501. [DOI] [PubMed]
Grither WR, Longmore GD. Inhibition of tumor-microenvironment interaction and tumor invasion by small-molecule allosteric inhibitor of DDR2 extracellular domain.Proc Natl Acad Sci U S A. 2018;115:E7786–94. [DOI] [PubMed] [PMC]
Mahul-Mellier A, Fauvet B, Gysbers A, Dikiy I, Oueslati A, Georgeon S, et al. c-Abl phosphorylates α-synuclein and regulates its degradation: implication for α-synuclein clearance and contribution to the pathogenesis of Parkinson’s disease.Hum Mol Genet. 2014;23:2858–79. [DOI] [PubMed] [PMC]
Ko HS, Lee Y, Shin J, Karuppagounder SS, Gadad BS, Koleske AJ, et al. Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin’s ubiquitination and protective function.Proc Natl Acad Sci U S A. 2010;107:16691–6. [DOI] [PubMed] [PMC]
Karim MR, Liao EE, Kim J, Meints J, Martinez HM, Pletnikova O, et al. α-Synucleinopathy associated c-Abl activation causes p53-dependent autophagy impairment.Mol Neurodegener. 2020;15:27. [DOI] [PubMed] [PMC]
Lee S, Kim S, Park YJ, Yun SP, Kwon S, Kim D, et al. The c-Abl inhibitor, Radotinib HCl, is neuroprotective in a preclinical Parkinson’s disease mouse model.Hum Mol Genet. 2018;27:2344–56. [DOI] [PubMed] [PMC]
Zou F, Carrasquillo MM, Pankratz VS, Belbin O, Morgan K, Allen M, et al. Gene expression levels as endophenotypes in genome-wide association studies of Alzheimer disease.Neurology. 2010;74:480–6. [DOI] [PubMed] [PMC]
Tanabe A, Yamamura Y, Kasahara J, Morigaki R, Kaji R, Goto S. A novel tyrosine kinase inhibitor AMN107 (nilotinib) normalizes striatal motor behaviors in a mouse model of Parkinson’s disease.Front Cell Neurosci. 2014;8:50. [DOI] [PubMed] [PMC]
Lee S, Ryu HG, Kweon SH, Kim H, Park H, Lee K, et al. c-Abl Regulates the Pathological Deposition of TDP-43 via Tyrosine 43 Phosphorylation.Cells. 2022;11:3972. [DOI] [PubMed] [PMC]
Wylie AA, Schoepfer J, Jahnke W, Cowan-Jacob SW, Loo A, Furet P, et al. The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1.Nature. 2017;543:733–7. [DOI] [PubMed]
Schoepfer J, Jahnke W, Berellini G, Buonamici S, Cotesta S, Cowan-Jacob SW, et al. Discovery of Asciminib (ABL001), an Allosteric Inhibitor of the Tyrosine Kinase Activity of BCR-ABL1.J Med Chem. 2018;61:8120–35. [DOI] [PubMed]
Ashpole NM, Song W, Brustovetsky T, Engleman EA, Brustovetsky N, Cummins TR, et al. Calcium/calmodulin-dependent protein kinase II (CaMKII) inhibition induces neurotoxicity via dysregulation of glutamate/calcium signaling and hyperexcitability.J Biol Chem. 2012;287:8495–506. [DOI] [PubMed] [PMC]
Wang R, Yin Y, Mahmood Q, Wang X, Gao Y, Gou G, et al. Calmodulin inhibitor ameliorates cognitive dysfunction via inhibiting nitrosative stress and NLRP3 signaling in mice with bilateral carotid artery stenosis.CNS Neurosci Ther. 2017;23:818–26. [DOI] [PubMed] [PMC]
Novak G, Seeman P. Hyperactive mice show elevated D2High receptors, a model for schizophrenia: Calcium/calmodulin-dependent kinase II alpha knockouts.Synapse. 2010;64:794–800. [DOI] [PubMed]
Salado IG, Redondo M, Bello ML, Perez C, Liachko NF, Kraemer BC, et al. Protein kinase CK-1 inhibitors as new potential drugs for amyotrophic lateral sclerosis.J Med Chem. 2014;57:2755–72. [DOI] [PubMed] [PMC]
Alquezar C, Salado IG, Encarnación Adl, Pérez DI, Moreno F, Gil C, et al. Targeting TDP-43 phosphorylation by Casein Kinase-1δ inhibitors: a novel strategy for the treatment of frontotemporal dementia.Mol Neurodegener. 2016;11:36. [DOI] [PubMed] [PMC]
Martínez-González L, Rodríguez-Cueto C, Cabezudo D, Bartolomé F, Andrés-Benito P, Ferrer I, et al. Motor neuron preservation and decrease of in vivo TDP-43 phosphorylation by protein CK-1δ kinase inhibitor treatment.Sci Rep. 2020;10:4449. [DOI] [PubMed] [PMC]
Wager TT, Galatsis P, Chandrasekaran RY, Butler TW, Li J, Zhang L, et al. Identification and Profiling of a Selective and Brain Penetrant Radioligand for in Vivo Target Occupancy Measurement of Casein Kinase 1 (CK1) Inhibitors.ACS Chem Neurosci. 2017;8:1995–2004. [DOI] [PubMed]
Mente S, Arnold E, Butler T, Chakrapani S, Chandrasekaran R, Cherry K, et al. Ligand-protein interactions of selective casein kinase 1δ inhibitors.J Med Chem. 2013;56:6819–28. [DOI] [PubMed]
Rehfeldt SCH, Laufer S, Goettert MI. A Highly Selective In Vitro JNK3 Inhibitor, FMU200, Restores Mitochondrial Membrane Potential and Reduces Oxidative Stress and Apoptosis in SH-SY5Y Cells.Int J Mol Sci. 2021;22:3701. [DOI] [PubMed] [PMC]
Bain J, McLauchlan H, Elliott M, Cohen P. The specificities of protein kinase inhibitors: an update.Biochem J. 2003;371:199–204. [DOI] [PubMed] [PMC]
Choi W, Abel G, Klintworth H, Flavell RA, Xia Z. JNK3 mediates paraquat- and rotenone-induced dopaminergic neuron death.J Neuropathol Exp Neurol. 2010;69:511–20. [DOI] [PubMed] [PMC]
Liu J, Hu H, Wu B. RIPK1 inhibitor ameliorates the MPP+/MPTP-induced Parkinson’s disease through the ASK1/JNK signalling pathway.Brain Res. 2021;1757:147310. [DOI] [PubMed]
Wang Y, Zhang Y, Wei Z, Li H, Zhou H, Zhang Z, et al. JNK inhibitor protects dopaminergic neurons by reducing COX-2 expression in the MPTP mouse model of subacute Parkinson’s disease.J Neurol Sci. 2009;285:172–7. [DOI] [PubMed]
Morfini GA, You Y, Pollema SL, Kaminska A, Liu K, Yoshioka K, et al. Pathogenic huntingtin inhibits fast axonal transport by activating JNK3 and phosphorylating kinesin.Nat Neurosci. 2009;12:864–71. [DOI] [PubMed] [PMC]
Perrin V, Dufour N, Raoul C, Hassig R, Brouillet E, Aebischer P, et al. Implication of the JNK pathway in a rat model of Huntington’s disease.Exp Neurol. 2009;215:191–200. [DOI] [PubMed]
Plotnikov MB, Chernysheva GA, Smolyakova VI, Aliev OI, Trofimova ES, Sherstoboev EY, et al. Neuroprotective Effects of a Novel Inhibitor of c-Jun N-Terminal Kinase in the Rat Model of Transient Focal Cerebral Ischemia.Cells. 2020;9:1860. [DOI] [PubMed] [PMC]
Chen Q, Tu Y, Mak S, Chen J, Lu J, Chen C, et al. Discovery of a novel small molecule PT109 with multi-targeted effects against Alzheimer’s disease in vitro and in vivo.Eur J Pharmacol. 2020;883:173361. [DOI] [PubMed]
Baier A, Szyszka R. Compounds from Natural Sources as Protein Kinase Inhibitors.Biomolecules. 2020;10:1546. [DOI] [PubMed] [PMC]
Wu Y, Zhao Y, Guan Z, Esmaeili S, Xiao Z, Kuriakose D. JNK3 inhibitors as promising pharmaceuticals with neuroprotective properties.Cell Adh Migr. 2024;18:1–11. [DOI] [PubMed] [PMC]
Matsuda S, Yasukawa T, Homma Y, Ito Y, Niikura T, Hiraki T, et al. c-Jun N-terminal kinase (JNK)-interacting protein-1b/islet-brain-1 scaffolds Alzheimer’s amyloid precursor protein with JNK.J Neurosci. 2001;21:6597–607. [DOI] [PubMed] [PMC]
Gower CM, Chang MEK, Maly DJ. Bivalent inhibitors of protein kinases.Crit Rev Biochem Mol Biol. 2014;49:102–15. [DOI] [PubMed] [PMC]
Quan Q, Li X, Feng J, Hou J, Li M, Zhang B. Ginsenoside Rg1 reduces β‑amyloid levels by inhibiting CDΚ5‑induced PPARγ phosphorylation in a neuron model of Alzheimer’s disease.Mol Med Rep. 2020;22:3277–88. [DOI]
Seo J, Kritskiy O, Watson LA, Barker SJ, Dey D, Raja WK, et al. Inhibition of p25/Cdk5 Attenuates Tauopathy in Mouse and iPSC Models of Frontotemporal Dementia.J Neurosci. 2017;37:9917–24. [DOI] [PubMed] [PMC]
Shen X, Luo T, Li S, Ting O, He F, Xu J, et al. Quercetin inhibits okadaic acid-induced tau protein hyperphosphorylation through the Ca2+‑calpain‑p25‑CDK5 pathway in HT22 cells.Int J Mol Med. 2018;41:1138–46. [DOI] [PubMed]
Zheng Y, Li B, Amin ND, Albers W, Pant HC. A peptide derived from cyclin-dependent kinase activator (p35) specifically inhibits Cdk5 activity and phosphorylation of tau protein in transfected cells.Eur J Biochem. 2002;269:4427–34. [DOI] [PubMed]
Corbel C, Zhang B, Parc AL, Baratte B, Colas P, Couturier C, et al. Tamoxifen inhibits CDK5 kinase activity by interacting with p35/p25 and modulates the pattern of tau phosphorylation.Chem Biol. 2015;22:472–82. [DOI] [PubMed]
Qu C, Li Q, Su Z, Ip S, Yuan Q, Xie Y, et al. Nano-Honokiol ameliorates the cognitive deficits in TgCRND8 mice of Alzheimer’s disease via inhibiting neuropathology and modulating gut microbiota.J Adv Res. 2021;35:231–43. [DOI] [PubMed] [PMC]
Jiao Y, Zhang J, Qiao W, Tian S, Wang Y, Wang C, et al. Kai-Xin-San Inhibits Tau Pathology and Neuronal Apoptosis in Aged SAMP8 Mice.Mol Neurobiol. 2022;59:3294–309. [DOI] [PubMed] [PMC]
Shukla V, Seo J, Binukumar BK, Amin ND, Reddy P, Grant P, et al. TFP5, a Peptide Inhibitor of Aberrant and Hyperactive Cdk5/p25, Attenuates Pathological Phenotypes and Restores Synaptic Function in CK-p25Tg Mice.J Alzheimers Dis. 2017;56:335–49. [DOI] [PubMed] [PMC]
Zeb A, Kim D, Alam SI, Son M, Kumar R, Rampogu S, et al. Computational Simulations Identify Pyrrolidine-2,3-Dione Derivatives as Novel Inhibitors of Cdk5/p25 Complex to Attenuate Alzheimer’s Pathology.J Clin Med. 2019;8:746. [DOI] [PubMed] [PMC]
Zeb A, Son M, Yoon S, Kim JH, Park SJ, Lee KW. Computational Simulations Identified Two Candidate Inhibitors of Cdk5/p25 to Abrogate Tau-associated Neurological Disorders.Comput Struct Biotechnol J. 2019;17:579–90. [DOI] [PubMed] [PMC]
He R, Huang W, Huang Y, Xu M, Song P, Huang Y, et al. Cdk5 Inhibitory Peptide Prevents Loss of Dopaminergic Neurons and Alleviates Behavioral Changes in an MPTP Induced Parkinson’s Disease Mouse Model.Front Aging Neurosci. 2018;10:162. [DOI] [PubMed] [PMC]
Reudhabibadh R, Binlateh T, Chonpathompikunlert P, Nonpanya N, Prommeenate P, Chanvorachote P, et al. Suppressing Cdk5 Activity by Luteolin Inhibits MPP+-Induced Apoptotic of Neuroblastoma through Erk/Drp1 and Fak/Akt/GSK3β Pathways.Molecules. 2021;26:1307. [DOI] [PubMed] [PMC]
Chergui K, Svenningsson P, Greengard P. Cyclin-dependent kinase 5 regulates dopaminergic and glutamatergic transmission in the striatum.Proc Natl Acad Sci U S A. 2004;101:2191–6. [DOI] [PubMed] [PMC]
Bignante EA, Paglini G, Molina VA. Previous stress exposure enhances both anxiety-like behaviour and p35 levels in the basolateral amygdala complex: modulation by midazolam.Eur Neuropsychopharmacol. 2010;20:388–97. [DOI] [PubMed]
Umfress A, Singh S, Ryan KJ, Chakraborti A, Plattner F, Sonawane Y, et al. Systemic Administration of a Brain Permeable Cdk5 Inhibitor Alters Neurobehavior.Front Pharmacol. 2022;13:863762. [DOI] [PubMed] [PMC]
Liu X, Lai L, Chen J, Li X, Wang N, Zhou L, et al. An inhibitor with GSK3β and DYRK1A dual inhibitory properties reduces Tau hyperphosphorylation and ameliorates disease in models of Alzheimer’s disease.Neuropharmacology. 2023;232:109525. [DOI] [PubMed]
Zhu B, Parsons T, Foley C, Shaw Y, Dunckley T, Hulme C, et al. DYRK1A antagonists rescue degeneration and behavioural deficits of in vivo models based on amyloid-β, Tau and DYRK1A neurotoxicity.Sci Rep. 2022;12:15847. [DOI] [PubMed] [PMC]
Souchet B, Audrain M, Billard JM, Dairou J, Fol R, Orefice NS, et al. Inhibition of DYRK1A proteolysis modifies its kinase specificity and rescues Alzheimer phenotype in APP/PS1 mice.Acta Neuropathol Commun. 2019;7:46. [DOI] [PubMed] [PMC]
Kim J, Kim S, Jeong H, Park J, Moon M, Hoe H. Inhibiting EGFR/HER-2 ameliorates neuroinflammatory responses and the early stage of tau pathology through DYRK1A.Front Immunol. 2022;13:903309. [DOI] [PubMed] [PMC]
Liu W, Liu X, Tian L, Gao Y, Liu W, Chen H, et al. Design, synthesis and biological evaluation of harmine derivatives as potent GSK-3β/DYRK1A dual inhibitors for the treatment of Alzheimer’s disease.Eur J Med Chem. 2021;222:113554. [DOI] [PubMed]
Kargbo RB. Selective DYRK1A Inhibitor for the Treatment of Neurodegenerative Diseases: Alzheimer, Parkinson, Huntington, and Down Syndrome.ACS Med Chem Lett. 2020;11:1795–96. [DOI] [PubMed] [PMC]
AlNajjar YT, Gabr M, ElHady AK, Salah M, Wilms G, Abadi AH, et al. Discovery of novel 6-hydroxybenzothiazole urea derivatives as dual Dyrk1A/α-synuclein aggregation inhibitors with neuroprotective effects.Eur J Med Chem. 2022;227:113911. [DOI] [PubMed]
Habib MZ, Tadros MG, Abd-Alkhalek HA, Mohamad MI, Eid DM, Hassan FE, et al. Harmine prevents 3-nitropropionic acid-induced neurotoxicity in rats via enhancing NRF2-mediated signaling: Involvement of p21 and AMPK.Eur J Pharmacol. 2022;927:175046. [DOI] [PubMed]
Santini E, Valjent E, Usiello A, Carta M, Borgkvist A, Girault J, et al. Critical involvement of cAMP/DARPP-32 and extracellular signal-regulated protein kinase signaling in L-DOPA-induced dyskinesia.J Neurosci. 2007;27:6995–7005. [DOI] [PubMed] [PMC]
Tassin TC, Benavides DR, Plattner F, Nishi A, Bibb JA. Regulation of ERK Kinase by MEK1 Kinase Inhibition in the Brain.J Biol Chem. 2015;290:16319–29. [DOI] [PubMed] [PMC]
Leow CC, Gerondakis S, Spencer A. MEK inhibitors as a chemotherapeutic intervention in multiple myeloma.Blood Cancer J. 2013;3:e105. [DOI] [PubMed] [PMC]
Wang JQ, Mao L. The ERK Pathway: Molecular Mechanisms and Treatment of Depression.Mol Neurobiol. 2019;56:6197–205. [DOI] [PubMed] [PMC]
Qi X, Lin W, Wang D, Pan Y, Wang W, Sun M. A role for the extracellular signal-regulated kinase signal pathway in depressive-like behavior.Behav Brain Res. 2009;199:203–9. [DOI] [PubMed]
Tronson NC, Schrick C, Fischer A, Sananbenesi F, Pagès G, Pouysségur J, et al. Regulatory mechanisms of fear extinction and depression-like behavior.Neuropsychopharmacology. 2008;33:1570–83. [DOI] [PubMed] [PMC]
Satoh Y, Endo S, Nakata T, Kobayashi Y, Yamada K, Ikeda T, et al. ERK2 contributes to the control of social behaviors in mice.J Neurosci. 2011;31:11953–67. [DOI] [PubMed] [PMC]
Nguyen LH, Leiser SC, Song D, Brunner D, Roberds SL, Wong M, et al. Inhibition of MEK-ERK signaling reduces seizures in two mouse models of tuberous sclerosis complex.Epilepsy Res. 2022;181:106890. [DOI] [PubMed] [PMC]
Adviento B, Corbin IL, Widjaja F, Desachy G, Enrique N, Rosser T, et al. Autism traits in the RASopathies.J Med Genet. 2014;51:10–20. [DOI] [PubMed] [PMC]
Murari K, Abushaibah A, Rho JM, Turner RW, Cheng N. A clinically relevant selective ERK-pathway inhibitor reverses core deficits in a mouse model of autism.EBioMedicine. 2023;91:104565. [DOI] [PubMed] [PMC]
Sun X, Liu Y, Liu B, Xiao Z, Zhang L. Rolipram promotes remyelination possibly via MEK-ERK signal pathway in cuprizone-induced demyelination mouse.Exp Neurol. 2012;237:304–11. [DOI] [PubMed]
Sahu R, Upadhayay S, Mehan S. Inhibition of extracellular regulated kinase (ERK)-1/2 signaling pathway in the prevention of ALS: Target inhibitors and influences on neurological dysfunctions.Eur J Cell Biol. 2021;100:151179. [DOI] [PubMed]
Chen Y, Zhang R, Xue F, Wang H, Chen Y, Hu G, et al. Quetiapine and repetitive transcranial magnetic stimulation ameliorate depression-like behaviors and up-regulate the proliferation of hippocampal-derived neural stem cells in a rat model of depression: The involvement of the BDNF/ERK signal pathway.Pharmacol Biochem Behav. 2015;136:39–46. [DOI] [PubMed]
Avrahami L, Farfara D, Shaham-Kol M, Vassar R, Frenkel D, Eldar-Finkelman H. Inhibition of glycogen synthase kinase-3 ameliorates β-amyloid pathology and restores lysosomal acidification and mammalian target of rapamycin activity in the Alzheimer disease mouse model: in vivo and in vitro studies.J Biol Chem. 2013;288:1295–306. [DOI] [PubMed] [PMC]
Duka T, Duka V, Joyce JN, Sidhu A. α-Synuclein contributes to GSK-3β-catalyzed Tau phosphorylation in Parkinson’s disease models.FASEB J. 2009;23:2820–30. [DOI] [PubMed] [PMC]
Wills J, Credle J, Haggerty T, Lee J, Oaks AW, Sidhu A. Tauopathic changes in the striatum of A53T α-synuclein mutant mouse model of Parkinson’s disease.PLoS One. 2011;6:e17953. [DOI] [PubMed] [PMC]
L’Episcopo F, Drouin-Ouellet J, Tirolo C, Pulvirenti A, Giugno R, Testa N, et al. GSK-3β-induced Tau pathology drives hippocampal neuronal cell death in Huntington’s disease: involvement of astrocyte-neuron interactions.Cell Death Dis. 2016;7:e2206. [DOI] [PubMed] [PMC]
Rippin I, Bonder K, Joseph S, Sarsor A, Vaks L, Eldar-Finkelman H. Inhibition of GSK-3 ameliorates the pathogenesis of Huntington’s disease.Neurobiol Dis. 2021;154:105336. [DOI] [PubMed]
Martínez-González L, Gonzalo-Consuegra C, Gómez-Almería M, Porras G, De Lago E, Martín-Requero Á, et al. Tideglusib, a Non-ATP Competitive Inhibitor of GSK-3β as a Drug Candidate for the Treatment of Amyotrophic Lateral Sclerosis.Int J Mol Sci. 2021;22:8975. [DOI] [PubMed] [PMC]
Licht-Murava A, Paz R, Vaks L, Avrahami L, Plotkin B, Eisenstein M, et al. A unique type of GSK-3 inhibitor brings new opportunities to the clinic.Sci Signal. 2016;9:ra110. [DOI] [PubMed]
Pardo M, Cheng Y, Velmeshev D, Magistri M, Eldar-Finkelman H, Martinez A, et al. Intranasal siRNA administration reveals IGF2 deficiency contributes to impaired cognition in Fragile X syndrome mice.JCI Insight. 2017;2:e91782. [DOI] [PubMed] [PMC]
Freland L, Beaulieu J. Inhibition of GSK3 by lithium, from single molecules to signaling networks.Front Mol Neurosci. 2012;5:14. [DOI] [PubMed] [PMC]
Kang UG, Roh M, Jung J, Shin SY, Lee YH, Park J, et al. Activation of protein kinase B (Akt) signaling after electroconvulsive shock in the rat hippocampus.Prog Neuropsychopharmacol Biol Psychiatry. 2004;28:41–4. [DOI] [PubMed]
Gould TD. Targeting glycogen synthase kinase-3 as an approach to develop novel mood-stabilising medications.Expert Opin Ther Targets. 2006;10:377–92. [DOI] [PubMed]
Kaidanovich-Beilin O, Milman A, Weizman A, Pick CG, Eldar-Finkelman H. Rapid antidepressive-like activity of specific glycogen synthase kinase-3 inhibitor and its effect on β-catenin in mouse hippocampus.Biol Psychiatry. 2004;55:781–4. [DOI] [PubMed]
Cheng Y, Desse S, Martinez A, Worthen RJ, Jope RS, Beurel E. TNFα disrupts blood brain barrier integrity to maintain prolonged depressive-like behavior in mice.Brain Behav Immun. 2018;69:556–67. [DOI] [PubMed] [PMC]
Liu R, Fuchikami M, Dwyer JM, Lepack AE, Duman RS, Aghajanian GK. GSK-3 inhibition potentiates the synaptogenic and antidepressant-like effects of subthreshold doses of ketamine.Neuropsychopharmacology. 2013;38:2268–77. [DOI] [PubMed] [PMC]
Griebel G, Stemmelin J, Lopez-Grancha M, Boulay D, Boquet G, Slowinski F, et al. The selective GSK3 inhibitor, SAR502250, displays neuroprotective activity and attenuates behavioral impairments in models of neuropsychiatric symptoms of Alzheimer's disease in rodents.Sci Rep. 2019;9:18045. [DOI] [PubMed] [PMC]
Capurro V, Lanfranco M, Summa M, Porceddu PF, Ciampoli M, Margaroli N, et al. The mood stabilizing properties of AF3581, a novel potent GSK-3β inhibitor.Biomed Pharmacother. 2020;128:110249. [DOI] [PubMed]
Spilman P, Podlutskaya N, Hart MJ, Debnath J, Gorostiza O, Bredesen D, et al. Inhibition of mTOR by Rapamycin Abolishes Cognitive Deficits and Reduces Amyloid-β Levels in a Mouse Model of Alzheimer’s Disease.PLoS One. 2010;5:e9979. [DOI] [PubMed] [PMC]
Majumder S, Richardson A, Strong R, Oddo S. Inducing autophagy by rapamycin before, but not after, the formation of plaques and tangles ameliorates cognitive deficits.PLoS One. 2011;6:e25416. [DOI] [PubMed] [PMC]
Santini E, Heiman M, Greengard P, Valjent E, Fisone G. Inhibition of mTOR signaling in Parkinson’s disease prevents L-DOPA-induced dyskinesia.Sci Signal. 2009;2:ra36. [DOI] [PubMed]
Nguyen LH, Bordey A. Current Review in Basic Science: Animal Models of Focal Cortical Dysplasia and Epilepsy.Epilepsy Curr. 2022;22:234–40. [DOI] [PubMed] [PMC]
Zhang Z, Fan Q, Luo X, Lou K, Weiss WA, Shokat KM. Brain-restricted mTOR inhibition with binary pharmacology.Nature. 2022;609:822–8. [DOI] [PubMed] [PMC]
Sato A, Ikeda K. Genetic and Environmental Contributions to Autism Spectrum Disorder Through Mechanistic Target of Rapamycin.Biol Psychiatry Glob Open Sci. 2021;2:95–105. [DOI] [PubMed] [PMC]
Theoharides TC, Asadi S, Panagiotidou S. A case series of a luteolin formulation (NeuroProtek®) in children with autism spectrum disorders.Int J Immunopathol Pharmacol. 2012;25:317–23. [DOI] [PubMed]
Bhandari R, Kuhad A. Resveratrol suppresses neuroinflammation in the experimental paradigm of autism spectrum disorders.Neurochem Int. 2017;103:8–23. [DOI] [PubMed]
Thomas SD, Jha NK, Ojha S, Sadek B. mTOR Signaling Disruption and Its Association with the Development of Autism Spectrum Disorder.Molecules. 2023;28:1889. [DOI] [PubMed] [PMC]
Ferrer I, Blanco R, Carmona M, Puig B, Barrachina M, Gómez C, et al. Active, phosphorylation-dependent mitogen-activated protein kinase (MAPK/ERK), stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and p38 kinase expression in Parkinson's disease and Dementia with Lewy bodies.J Neural Transm (Vienna). 2001;108:1383–96. [DOI] [PubMed]
Tsirigotis M, Baldwin RM, Tang MY, Lorimer IAJ, Gray DA. Activation of p38MAPK contributes to expanded polyglutamine-induced cytotoxicity.PLoS One. 2008;3:e2130. [DOI] [PubMed] [PMC]
Taylor DM, Moser R, Régulier E, Breuillaud L, Dixon M, Beesen AA, et al. MAP kinase phosphatase 1 (MKP-1/DUSP1) is neuroprotective in Huntington’s disease via additive effects of JNK and p38 inhibition.J Neurosci. 2013;33:2313–25. [DOI] [PubMed] [PMC]
Menon MB, Dhamija S, Kotlyarov A, Gaestel M. The problem of pyridinyl imidazole class inhibitors of MAPK14/p38α and MAPK11/p38β in autophagy research.Autophagy. 2015;11:1425–7. [DOI] [PubMed] [PMC]
Fabian MA, 3rd WHB, Treiber DK, Atteridge CE, Azimioara MD, Benedetti MG, et al. A small molecule-kinase interaction map for clinical kinase inhibitors.Nat Biotechnol. 2005;23:329–36. [DOI] [PubMed]
Bazuine M, Carlotti F, Tafrechi RSJ, Hoeben RC, Maassen JA. Mitogen-activated protein kinase (MAPK) phosphatase-1 and -4 attenuate p38 MAPK during dexamethasone-induced insulin resistance in 3T3-L1 adipocytes.Mol Endocrinol. 2004;18:1697–707. [DOI] [PubMed]
Alam J, Blackburn K, Patrick D. Neflamapimod: Clinical Phase 2b-Ready Oral Small Molecule Inhibitor of p38α to Reverse Synaptic Dysfunction in Early Alzheimer’s Disease.J Prev Alzheimers Dis. 2017;4:273–8. [DOI] [PubMed]
Jiang Y, Alam JJ, Gomperts SN, Maruff P, Lemstra AW, Germann UA, et al. Preclinical and randomized clinical evaluation of the p38α kinase inhibitor neflamapimod for basal forebrain cholinergic degeneration.Nat Commun. 2022;13:5308. [DOI] [PubMed] [PMC]
Parsons RG, Davis M. A metaplasticity-like mechanism supports the selection of fear memories: role of protein kinase a in the amygdala.J Neurosci. 2012;32:7843–51. [DOI] [PubMed] [PMC]
Pandey SC, Zhang H, Roy A, Xu T. Deficits in amygdaloid cAMP-responsive element-binding protein signaling play a role in genetic predisposition to anxiety and alcoholism.J Clin Invest. 2005;115:2762–73. [DOI] [PubMed] [PMC]
Glebov-McCloud AGP, Saide WS, Gaine ME, Strack S. Protein Kinase A in neurological disorders.J Neurodev Disord. 2024;16:9. [DOI] [PubMed] [PMC]
Nelson TJ, Sun M, Lim C, Sen A, Khan T, Chirila FV, et al. Bryostatin Effects on Cognitive Function and PKCɛ in Alzheimer’s Disease Phase IIa and Expanded Access Trials.J Alzheimers Dis. 2017;58:521–35. [DOI] [PubMed] [PMC]
Farlow MR, Thompson RE, Wei L, Tuchman AJ, Grenier E, Crockford D, et al. A Randomized, Double-Blind, Placebo-Controlled, Phase II Study Assessing Safety, Tolerability, and Efficacy of Bryostatin in the Treatment of Moderately Severe to Severe Alzheimer’s Disease.J Alzheimers Dis. 2019;67:555–70. [DOI] [PubMed] [PMC]
Schrenk K, Kapfhammer JP, Metzger F. Altered dendritic development of cerebellar Purkinje cells in slice cultures from protein kinase Cgamma-deficient mice.Neuroscience. 2002;110:675–89. [DOI] [PubMed]
Ghoumari AM, Wehrlé R, Zeeuw CID, Sotelo C, Dusart I. Inhibition of protein kinase C prevents Purkinje cell death but does not affect axonal regeneration.J Neurosci. 2002;22:3531–42. [DOI] [PubMed] [PMC]
Chen G, Manji HK, Hawver DB, Wright CB, Potter WZ. Chronic Sodium Valproate Selectively Decreases Protein Kinase C α and ε In Vitro.J Neurochem. 1994;63:2361–4. [DOI] [PubMed]
Chen G, Masana MI, Manji HK. Lithium regulates PKC-mediated intracellular cross-talk and gene expression in the CNS in vivo.Bipolar Disord. 2000;2:217–36. [DOI] [PubMed]
Hahn CG, Friedman E. Abnormalities in protein kinase C signaling and the pathophysiology of bipolar disorder.Bipolar Disord. 1999;1:81–6. [DOI] [PubMed]
Szabo ST, Machado-Vieira R, Yuan P, Wang Y, Wei Y, Falke C, et al. Glutamate receptors as targets of protein kinase C in the pathophysiology and treatment of animal models of mania.Neuropharmacology. 2009;56:47–55. [DOI] [PubMed] [PMC]
Pereira M, Andreatini R, Schwarting RKW, Brenes JC. Amphetamine-induced appetitive 50-kHz calls in rats: a marker of affect in mania?Psychopharmacology (Berl). 2014;231:2567–77. [DOI] [PubMed]
Bebchuk JM, Arfken CL, Dolan-Manji S, Murphy J, Hasanat K, Manji HK. A preliminary investigation of a protein kinase C inhibitor in the treatment of acute mania.Arch Gen Psychiatry. 2000;57:95–7. [DOI] [PubMed]
Kulkarni J, Garland KA, Scaffidi A, Headey B, Anderson R, Castella Ad, et al. A pilot study of hormone modulation as a new treatment for mania in women with bipolar affective disorder.Psychoneuroendocrinology. 2006;31:543–7. [DOI] [PubMed]
Ahmad A, Sheikh S, Shah T, Reddy MS, Prasad B, Verma KK, et al. Endoxifen, a New Treatment Option for Mania: A Double-Blind, Active-Controlled Trial Demonstrates the Antimanic Efficacy of Endoxifen.Clin Transl Sci. 2016;9:252–9. [DOI] [PubMed] [PMC]
Zhu S, Zhang Y, Bai G, Li H. Necrostatin-1 ameliorates symptoms in R6/2 transgenic mouse model of Huntington’s disease.Cell Death Dis. 2011;2:e115. [DOI] [PubMed] [PMC]
Lin Q, Chen P, Wang W, Lin C, Zhou Y, Yu L, et al. RIP1/RIP3/MLKL mediates dopaminergic neuron necroptosis in a mouse model of Parkinson disease.Lab Invest. 2020;100:503–11. [DOI] [PubMed]
Vissers MFJM, Heuberger JAAC, Groeneveld GJ, Nijhuis JO, Deyn PPD, Hadi S, et al. Safety, pharmacokinetics and target engagement of novel RIPK1 inhibitor SAR443060 (DNL747) for neurodegenerative disorders: Randomized, placebo-controlled, double-blind phase I/Ib studies in healthy subjects and patients.Clin Transl Sci. 2022;15:2010–23. [DOI] [PubMed] [PMC]
Benn CL, Dawson LA. Clinically Precedented Protein Kinases: Rationale for Their Use in Neurodegenerative Disease.Front Aging Neurosci. 2020;12:242. [DOI] [PubMed] [PMC]
Lingor P, Weber M, Camu W, Friede T, Hilgers R, Leha A, et al.; ROCK-ALS Investigators. ROCK-ALS: Protocol for a Randomized, Placebo-Controlled, Double-Blind Phase IIa Trial of Safety, Tolerability and Efficacy of the Rho Kinase (ROCK) Inhibitor Fasudil in Amyotrophic Lateral Sclerosis.Front Neurol. 2019;10:293. [DOI] [PubMed] [PMC]
Patel S, Meilandt WJ, Erickson RI, Chen J, Deshmukh G, Estrada AA, et al. Selective Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12) with Activity in a Model of Alzheimer’s Disease.J Med Chem. 2017;60:8083–102. [DOI] [PubMed]
A Study of GDC-0134 to Determine Initial Safety, Tolerability, and Pharmacokinetic Parameters in Participants With Amyotrophic Lateral Sclerosis [Internet].[Cited 2024 Sep 13]. Available from: https://clinicaltrials.gov/study/NCT02655614
Tang X, Xing S, Ma M, Xu Z, Guan Q, Chen Y, et al. The Development and Design Strategy of Leucine-Rich Repeat Kinase 2 Inhibitors: Promising Therapeutic Agents for Parkinson’s Disease.J Med Chem. 2023;66:2282–307. [DOI] [PubMed]
Liu X, Kalogeropulou AF, Domingos S, Makukhin N, Nirujogi RS, Singh F, et al. Discovery of XL01126: A Potent, Fast, Cooperative, Selective, Orally Bioavailable, and Blood-Brain Barrier Penetrant PROTAC Degrader of Leucine-Rich Repeat Kinase 2.J Am Chem Soc. 2022;144:16930–52. [DOI] [PubMed] [PMC]
West AB. Achieving neuroprotection with LRRK2 kinase inhibitors in Parkinson disease.Exp Neurol. 2017;298:236–45. [DOI] [PubMed] [PMC]
Taymans J, Vancraenenbroeck R, Ollikainen P, Beilina A, Lobbestael E, Maeyer MD, et al. LRRK2 kinase activity is dependent on LRRK2 GTP binding capacity but independent of LRRK2 GTP binding.PLoS One. 2011;6:e23207. [DOI] [PubMed] [PMC]
Schaffner A, Li X, Gomez-Llorente Y, Leandrou E, Memou A, Clemente N, et al. Vitamin B12 modulates Parkinson’s disease LRRK2 kinase activity through allosteric regulation and confers neuroprotection.Cell Res. 2019;29:313–29. [DOI] [PubMed] [PMC]
Estrada AA, Liu X, Baker-Glenn C, Beresford A, Burdick DJ, Chambers M, et al. Discovery of highly potent, selective, and brain-penetrable leucine-rich repeat kinase 2 (LRRK2) small molecule inhibitors.J Med Chem. 2012;55:9416–33. [DOI] [PubMed]
Baptista MAS, Merchant K, Barrett T, Bhargava S, Bryce DK, Ellis JM, et al. LRRK2 inhibitors induce reversible changes in nonhuman primate lungs without measurable pulmonary deficits.Sci Transl Med. 2020;12:eaav0820. [DOI] [PubMed]
Zhao HT, John N, Delic V, Ikeda-Lee K, Kim A, Weihofen A, et al. LRRK2 Antisense Oligonucleotides Ameliorate α-Synuclein Inclusion Formation in a Parkinson’s Disease Mouse Model.Mol Ther Nucleic Acids. 2017;8:508–19. [DOI] [PubMed] [PMC]
Zhu H, Hixson P, Ma W, Sun J. Pharmacology of LRRK2 with type I and II kinase inhibitors revealed by cryo-EM.Cell Discov. 2024;10:10. [DOI] [PubMed] [PMC]
Brahmachari S, Ge P, Lee SH, Kim D, Karuppagounder SS, Kumar M, et al. Activation of tyrosine kinase c-Abl contributes to α-synuclein-induced neurodegeneration.J Clin Invest. 2016;126:2970–88. [DOI] [PubMed] [PMC]
Agami R, Blandino G, Oren M, Shaul Y. Interaction of c-Abl and p73α and their collaboration to induce apoptosis.Nature. 1999;399:809–13. [DOI] [PubMed]
Schlatterer SD, Tremblay MA, Acker CM, Davies P. Neuronal c-Abl overexpression leads to neuronal loss and neuroinflammation in the mouse forebrain.J Alzheimers Dis. 2011;25:119–33. [DOI] [PubMed] [PMC]
Feng L, Fu S, Yao Y, Li Y, Xu L, Zhao Y, et al. Roles for c-Abl in postoperative neurodegeneration.Int J Med Sci. 2022;19:1753–61. [DOI] [PubMed] [PMC]
Feng L, Sun Z, Liu Q, Ma T, Xu Z, Feng Z, et al. Propofol inhibits the expression of Abelson nonreceptor tyrosine kinase without affecting learning or memory function in neonatal rats.Brain Behav. 2020;10:e01810. [DOI] [PubMed] [PMC]
Chen L, Wang Z, Tang B, Fang M, Li J, Chen G, et al. Altered expression of c-Abl in patients with epilepsy and in a rat model.Synapse. 2014;68:306–16. [DOI] [PubMed]
Reichenstein M, Borovok N, Sheinin A, Brider T, Michaelevski I. Abelson Kinases Mediate the Depression of Spontaneous Synaptic Activity Induced by Amyloid Beta 1-42 Peptides.Cell Mol Neurobiol. 2021;41:431–48. [DOI] [PubMed]
Cancino GI, Toledo EM, Leal NR, Hernandez DE, Yévenes LF, Inestrosa NC, et al. STI571 prevents apoptosis, tau phosphorylation and behavioural impairments induced by Alzheimer’s β-amyloid deposits .Brain. 2008;131:2425–42. [DOI] [PubMed]
Estrada LD, Chamorro D, Yañez MJ, Gonzalez M, Leal N, Bernhardi Rv, et al. Reduction of Blood Amyloid-β Oligomers in Alzheimer’s Disease Transgenic Mice by c-Abl Kinase Inhibition.J Alzheimers Dis. 2016;54:1193–205. [DOI] [PubMed]
Basheer N, Smolek T, Hassan I, Liu F, Iqbal K, Zilka N, et al. Does modulation of tau hyperphosphorylation represent a reasonable therapeutic strategy for Alzheimer’s disease? From preclinical studies to the clinical trials.Mol Psychiatry. 2023;28:2197–214. [DOI] [PubMed] [PMC]
Xu Z, Yang C. TDP-43-The key to understanding amyotrophic lateral sclerosis.Rare Dis. 2014;2:e944443. [DOI] [PubMed] [PMC]
Marín T, Dulcey AE, Campos F, Fuente Cdl, Acuña M, Castro J, et al. c-Abl Activation Linked to Autophagy-Lysosomal Dysfunction Contributes to Neurological Impairment in Niemann-Pick Type A Disease.Front Cell Dev Biol. 2022;10:844297. [DOI] [PubMed] [PMC]
Klein A, Maldonado C, Vargas LM, Gonzalez M, Robledo F, Arce KPd, et al. Oxidative stress activates the c-Abl/p73 proapoptotic pathway in Niemann-Pick type C neurons.Neurobiol Dis. 2011;41:209–18. [DOI] [PubMed]
Rojas F, Gonzalez D, Cortes N, Ampuero E, Hernández DE, Fritz E, et al. Reactive oxygen species trigger motoneuron death in non-cell-autonomous models of ALS through activation of c-Abl signaling.Front Cell Neurosci. 2015;9:203. [DOI] [PubMed] [PMC]
Amada N, Aihara K, Ravid R, Horie M. Reduction of NR1 and phosphorylated Ca2+/calmodulin-dependent protein kinase II levels in Alzheimer’s disease.Neuroreport. 2005;16:1809–13. [DOI] [PubMed]
Reese LC, Laezza F, Woltjer R, Taglialatela G. Dysregulated phosphorylation of Ca2+ /calmodulin-dependent protein kinase II-α in the hippocampus of subjects with mild cognitive impairment and Alzheimer’s disease.J Neurochem. 2011;119:791–804. [DOI] [PubMed] [PMC]
Gu Z, Liu W, Yan Z. β-Amyloid Impairs AMPA Receptor Trafficking and Function by Reducing Ca2+/Calmodulin-dependent Protein Kinase II Synaptic Distribution.J Biol Chem. 2009;284:10639–49. [DOI] [PubMed] [PMC]
McKee AC, Kosik KS, Kennedy MB, Kowall NW. Hippocampal neurons predisposed to neurofibrillary tangle formation are enriched in type II calcium/calmodulin-dependent protein kinase.J Neuropathol Exp Neurol. 1990;49:49–63. [DOI] [PubMed]
Gardoni F, Schrama LH, Kamal A, Gispen WH, Cattabeni F, Luca MD. Hippocampal synaptic plasticity involves competition between Ca2+/calmodulin-dependent protein kinase II and postsynaptic density 95 for binding to the NR2A subunit of the NMDA receptor.J Neurosci. 2001;21:1501–9. [DOI] [PubMed] [PMC]
Gardoni F, Bellone C, Viviani B, Marinovich M, Meli E, Pellegrini-Giampietro DE, et al. Lack of PSD-95 drives hippocampal neuronal cell death through activation of an αCaMKII transduction pathway.Eur J Neurosci. 2002;16:777–86. [DOI] [PubMed]
Kobayashi T, Nemoto S, Ishida K, Taguchi K, Matsumoto T, Kamata K. Involvement of CaM kinase II in the impairment of endothelial function and eNOS activity in aortas of Type 2 diabetic rats.Clin Sci (Lond). 2012;123:375–86. [DOI] [PubMed]
Cipolletta E, Monaco S, Maione AS, Vitiello L, Campiglia P, Pastore L, et al. Calmodulin-dependent kinase II mediates vascular smooth muscle cell proliferation and is potentiated by extracellular signal regulated kinase.Endocrinology. 2010;151:2747–59. [DOI] [PubMed] [PMC]
Reventun P, Sanchez-Esteban S, Cook A, Cuadrado I, Roza C, Moreno-Gomez-Toledano R, et al. Bisphenol A induces coronary endothelial cell necroptosis by activating RIP3/CamKII dependent pathway.Sci Rep. 2020;10:4190. [DOI] [PubMed] [PMC]
Novak G, Seeman P, Tallerico T. Increased expression of calcium/calmodulin-dependent protein kinase IIβ in frontal cortex in schizophrenia and depression.Synapse. 2006;59:61–8. [DOI] [PubMed]
Matas E, William DJF, Toro CT. Abnormal expression of post-synaptic proteins in prefrontal cortex of patients with schizophrenia.Neurosci Lett. 2021;745:135629. [DOI] [PubMed]
Yabuki Y, Wu L, Fukunaga K. Cognitive enhancer ST101 improves schizophrenia-like behaviors in neonatal ventral hippocampus-lesioned rats in association with improved CaMKII/PKC pathway.J Pharmacol Sci. 2019;140:263–72. [DOI] [PubMed]
Brown CN, Cook SG, Allen HF, Crosby KC, Singh T, Coultrap SJ, et al. Characterization of six CaMKIIα variants found in patients with schizophrenia.iScience. 2021;24:103184. [DOI] [PubMed] [PMC]
Onori MP, Woerden GMv. Role of calcium/calmodulin-dependent kinase 2 in neurodevelopmental disorders.Brain Res Bull. 2021;171:209–20. [DOI] [PubMed]
Li K, Zhou T, Liao L, Yang Z, Wong C, Henn F, et al. βCaMKII in lateral habenula mediates core symptoms of depression.Science. 2013;341:1016–20. [DOI] [PubMed] [PMC]
Robison AJ, Vialou V, Sun H, Labonte B, Golden SA, Dias C, et al. Fluoxetine epigenetically alters the CaMKIIα promoter in nucleus accumbens to regulate ΔFosB binding and antidepressant effects.Neuropsychopharmacology. 2014;39:1178–86. [DOI] [PubMed] [PMC]
Xing G, Russell S, Hough C, O’Grady J, Zhang L, Yang S, et al. Decreased prefrontal CaMKII α mRNA in bipolar illness.Neuroreport. 2002;13:501–5. [DOI] [PubMed]
Wen Y, Li B, Han F, Wang E, Shi Y. Dysfunction of calcium/calmodulin/CaM kinase IIα cascades in the medial prefrontal cortex in post-traumatic stress disorder.Mol Med Rep. 2012;6:1140–4. [DOI] [PubMed]
Miller RL, Dhavale DD, O’Shea JY, Andruska KM, Liu J, Franklin EE, et al. Quantifying regional α -synuclein, amyloid β, and tau accumulation in lewy body dementia.Ann Clin Transl Neurol. 2022;9:106–21. [DOI] [PubMed] [PMC]
Catarzi D, Varano F, Vigiani E, Lambertucci C, Spinaci A, Volpini R, et al. Casein Kinase 1δ Inhibitors as Promising Therapeutic Agents for Neurodegenerative Disorders.Curr Med Chem. 2022;29:4698–737. [DOI] [PubMed]
Varano F, Catarzi D, Calenda S, Vigiani E, Colotta V. CK1 delta inhibition: an emerging strategy to combat neurodegenerative diseases.Future Med Chem. 2022;14:1111–3. [DOI] [PubMed]
De Wit T, Baekelandt V, Lobbestael E. Inhibition of LRRK2 or Casein Kinase 1 Results in LRRK2 Protein Destabilization.Mol Neurobiol. 2019;56:5273–86. [DOI] [PubMed] [PMC]
Nonaka T, Suzuki G, Tanaka Y, Kametani F, Hirai S, Okado H, et al. Phosphorylation of TAR DNA-binding Protein of 43 kDa (TDP-43) by Truncated Casein Kinase 1δ Triggers Mislocalization and Accumulation of TDP-43.J Biol Chem. 2016;291:5473–83. [DOI] [PubMed] [PMC]
Kennaway DJ, Varcoe TJ, Voultsios A, Salkeld MD, Rattanatray L, Boden MJ. Acute inhibition of casein kinase 1δ/ε rapidly delays peripheral clock gene rhythms.Mol Cell Biochem. 2015;398:195–206. [DOI] [PubMed]
Brennan KC, Bates EA, Shapiro RE, Zyuzin J, Hallows WC, Huang Y, et al. Casein kinase iδ mutations in familial migraine and advanced sleep phase.Sci Transl Med. 2013;5:183ra56, 1–11. [DOI] [PubMed] [PMC]
Xu Y, Padiath QS, Shapiro RE, Jones CR, Wu SC, Saigoh N, et al. Functional consequences of a CKIδ mutation causing familial advanced sleep phase syndrome.Nature. 2005;434:640–4. [DOI] [PubMed]
Yasojima K, Kuret J, DeMaggio AJ, McGeer E, McGeer PL. Casein kinase 1 delta mRNA is upregulated in Alzheimer disease brain.Brain Res. 2000;865:116–20. [DOI] [PubMed]
Hu MC, Qiu WR, Wang YP. JNK1, JNK2 and JNK3 are p53 N-terminal serine 34 kinases.Oncogene. 1997;15:2277–87. [DOI] [PubMed]
Musi CA, Agrò G, Santarella F, Iervasi E, Borsello T. JNK3 as Therapeutic Target and Biomarker in Neurodegenerative and Neurodevelopmental Brain Diseases.Cells. 2020;9:2190. [DOI] [PubMed] [PMC]
Salminen A, Kaarniranta K, Kauppinen A, Ojala J, Haapasalo A, Soininen H, et al. Impaired autophagy and APP processing in Alzheimer's disease: The potential role of Beclin 1 interactome.Prog Neurobiol. 2013;106–107:33–54. [DOI] [PubMed]
Tabas I, Ron D. Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress.Nat Cell Biol. 2011;13:184–90. [DOI] [PubMed] [PMC]
Puthalakath H, O’Reilly LA, Gunn P, Lee L, Kelly PN, Huntington ND, et al. ER stress triggers apoptosis by activating BH3-only protein Bim.Cell. 2007;129:1337–49. [DOI] [PubMed]
Gourmaud S, Paquet C, Dumurgier J, Pace C, Bouras C, Gray F, et al. Increased levels of cerebrospinal fluid JNK3 associated with amyloid pathology: links to cognitive decline.J Psychiatry Neurosci. 2015;40:151–61. [DOI] [PubMed] [PMC]
Sclip A, Antoniou X, Colombo A, Camici GG, Pozzi L, Cardinetti D, et al. c-Jun N-terminal kinase regulates soluble Aβ oligomers and cognitive impairment in AD mouse model.J Biol Chem. 2011;286:43871–80. [DOI] [PubMed] [PMC]
Sclip A, Arnaboldi A, Colombo I, Veglianese P, Colombo L, Messa M, et al. Soluble Aβ oligomer-induced synaptopathy: c-Jun N-terminal kinase's role.J Mol Cell Biol. 2013;5:277–9. [DOI] [PubMed]
Costello DA, Herron CE. The role of c-Jun N-terminal kinase in the Aβ-mediated impairment of LTP and regulation of synaptic transmission in the hippocampus.Neuropharmacology. 2004;46:655–62. [DOI] [PubMed]
Colombo A, Bastone A, Ploia C, Sclip A, Salmona M, Forloni G, et al. JNK regulates APP cleavage and degradation in a model of Alzheimer’s disease.Neurobiol Dis. 2009;33:518–25. [DOI] [PubMed]
Quan Q, Qian Y, Li X, Li M. CDK5 Participates in Amyloid-β Production by Regulating PPARγ Phosphorylation in Primary Rat Hippocampal Neurons.J Alzheimers Dis. 2019;71:443–60. [DOI] [PubMed]
Filho HVR, Guerra JV, Cagliari R, Batista FAH, Maire AL, Oliveira PSL, et al. Exploring the mechanism of PPARγ phosphorylation mediated by CDK5.J Struct Biol. 2019;207:317–26. [DOI] [PubMed]
Cruz JC, Tseng H, Goldman JA, Shih H, Tsai L. Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles.Neuron. 2003;40:471–83. [DOI] [PubMed]
Laha JK, Zhang X, Qiao L, Liu M, Chatterjee S, Robinson S, et al. Structure-activity relationship study of 2,4-diaminothiazoles as Cdk5/p25 kinase inhibitors.Bioorg Med Chem Lett. 2011;21:2098–101. [DOI] [PubMed] [PMC]
He F, Qi G, Zhang Q, Cai H, Li T, Li M, et al. Quantitative Phosphoproteomic Analysis in Alpha-Synuclein Transgenic Mice Reveals the Involvement of Aberrant p25/Cdk5 Signaling in Early-stage Parkinson’s Disease.Cell Mol Neurobiol. 2020;40:897–909. [DOI] [PubMed]
Cheng X, Xu S, Zhang C, Qin K, Yan J, Shao X. The BRCC3 regulated by Cdk5 promotes the activation of neuronal NLRP3 inflammasome in Parkinson's disease models.Biochem Biophys Res Commun. 2020;522:647–54. [DOI] [PubMed]
Shukla AK, Spurrier J, Kuzina I, Giniger E. Hyperactive Innate Immunity Causes Degeneration of Dopamine Neurons upon Altering Activity of Cdk5.Cell Rep. 2019;26:131–44.e4. [DOI] [PubMed] [PMC]
Park J, Seo J, Won J, Yeo H, Ahn Y, Kim K, et al. Abnormal Mitochondria in a Non-human Primate Model of MPTP-induced Parkinson’s Disease: Drp1 and CDK5/p25 Signaling.Exp Neurobiol. 2019;28:414–24. [DOI] [PubMed] [PMC]
Eastwood SL. The synaptic pathology of schizophrenia: is aberrant neurodevelopment and plasticity to blame?Int Rev Neurobiol. 2004;59:47–72. [DOI] [PubMed]
Nissen C, Holz J, Blechert J, Feige B, Riemann D, Voderholzer U, et al. Learning as a model for neural plasticity in major depression.Biol Psychiatry. 2010;68:544–52. [DOI] [PubMed]
Kim SH, Ryan TA. CDK5 serves as a major control point in neurotransmitter release.Neuron. 2010;67:797–809. [DOI] [PubMed] [PMC]
Ramos-Miguel A, Meana JJ, García-Sevilla JA. Cyclin-dependent kinase-5 and p35/p25 activators in schizophrenia and major depression prefrontal cortex: basal contents and effects of psychotropic medications.Int J Neuropsychopharmacol. 2013;16:683–9. [DOI] [PubMed]
Fletcher AI, Shuang R, Giovannucci DR, Zhang L, Bittner MA, Stuenkel EL. Regulation of exocytosis by cyclin-dependent kinase 5 via phosphorylation of Munc18.J Biol Chem. 1999;274:4027–35. [DOI] [PubMed]
Shuang R, Zhang L, Fletcher A, Groblewski GE, Pevsner J, Stuenkel EL. Regulation of Munc-18/syntaxin 1A interaction by cyclin-dependent kinase 5 in nerve endings.J Biol Chem. 1998;273:4957–66. [DOI] [PubMed]
Gil-Pisa I, Munarriz-Cuezva E, Ramos-Miguel A, Urigüen L, Meana JJ, García-Sevilla JA. Regulation of munc18-1 and syntaxin-1A interactive partners in schizophrenia prefrontal cortex: down-regulation of munc18-1a isoform and 75 kDa SNARE complex after antipsychotic treatment.Int J Neuropsychopharmacol. 2012;15:573–88. [DOI] [PubMed]
Bignante EA, Manzanares PAR, Mlewski EC, Bertotto ME, Bussolino DF, Paglini G, et al. Involvement of septal Cdk5 in the emergence of excessive anxiety induced by stress.Eur Neuropsychopharmacol. 2008;18:578–88. [DOI] [PubMed]
Wegiel J, Gong C, Hwang Y. The role of DYRK1A in neurodegenerative diseases.FEBS J. 2011;278:236–45. [DOI] [PubMed] [PMC]
Lee M, Kao S, Lemere CA, Xia W, Tseng H, Zhou Y, et al. APP processing is regulated by cytoplasmic phosphorylation.J Cell Biol. 2003;163:83–95. [DOI] [PubMed] [PMC]
Liu F, Liang Z, Wegiel J, Hwang Y, Iqbal K, Grundke-Iqbal I, et al. Overexpression of Dyrk1A contributes to neurofibrillary degeneration in Down syndrome.FASEB J. 2008;22:3224–33. [DOI] [PubMed] [PMC]
Ryoo S, Cho H, Lee H, Jeong HK, Radnaabazar C, Kim Y, et al. Dual-specificity tyrosine(Y)-phosphorylation regulated kinase 1A-mediated phosphorylation of amyloid precursor protein: evidence for a functional link between Down syndrome and Alzheimer's disease.J Neurochem. 2008;104:1333–44. [DOI] [PubMed]
Woods YL, Cohen P, Becker W, Jakes R, Goedert M, Wang X, et al. The kinase DYRK phosphorylates protein-synthesis initiation factor eIF2Bɛ at Ser539 and the microtubule-associated protein tau at Thr212: potential role for DYRK as a glycogen synthase kinase 3-priming kinase .Biochem J. 2001;355:609–15. [DOI] [PubMed] [PMC]
Dang T, Duan WY, Yu B, Tong DL, Cheng C, Zhang YF, et al. Autism-associated Dyrk1a truncation mutants impair neuronal dendritic and spine growth and interfere with postnatal cortical development.Mol Psychiatry. 2018;23:747–58. [DOI] [PubMed] [PMC]
Raveau M, Shimohata A, Amano K, Miyamoto H, Yamakawa K. DYRK1A-haploinsufficiency in mice causes autistic-like features and febrile seizures.Neurobiol Dis. 2018;110:180–91. [DOI] [PubMed]
Kim EJ, Sung JY, Lee HJ, Rhim H, Hasegawa M, Iwatsubo T, et al. Dyrk1A Phosphorylates α-Synuclein and Enhances Intracellular Inclusion Formation.J Biol Chem. 2006;281:33250–7. [DOI] [PubMed]
Ihara M, Tomimoto H, Kitayama H, Morioka Y, Akiguchi I, Shibasaki H, et al. Association of the cytoskeletal GTP-binding protein Sept4/H5 with cytoplasmic inclusions found in Parkinson’s disease and other synucleinopathies.J Biol Chem. 2003;278:24095–102. [DOI] [PubMed]
Ihara M, Yamasaki N, Hagiwara A, Tanigaki A, Kitano A, Hikawa R, et al. Sept4, a Component of Presynaptic Scaffold and Lewy Bodies, Is Required for the Suppression of α-Synuclein Neurotoxicity.Neuron. 2007;53:519–33. [DOI] [PubMed]
Albert-Gascó H, Ros-Bernal F, Castillo-Gómez E, Olucha-Bordonau FE. MAP/ERK Signaling in Developing Cognitive and Emotional Function and Its Effect on Pathological and Neurodegenerative Processes.Int J Mol Sci. 2020;21:4471. [DOI] [PubMed] [PMC]
Rai SN, Dilnashin H, Birla H, Singh SS, Zahra W, Rathore AS, et al. The Role of PI3K/Akt and ERK in Neurodegenerative Disorders.Neurotox Res. 2019;35:775–95. [DOI] [PubMed]
Kim EK, Choi E. Compromised MAPK signaling in human diseases: an update.Arch Toxicol. 2015;89:867–82. [DOI] [PubMed]
Venezia V, Nizzari M, Repetto E, Violani E, Corsaro A, Thellung S, et al. Amyloid precursor protein modulates ERK-1 and -2 signaling.Ann N Y Acad Sci. 2006;1090:455–65. [DOI] [PubMed]
Liu Y, Qin L, Li G, Zhang W, An L, Liu B, et al. Dextromethorphan protects dopaminergic neurons against inflammation-mediated degeneration through inhibition of microglial activation.J Pharmacol Exp Ther. 2003;305:212–8. [DOI] [PubMed]
Sun J, Nan G. The extracellular signal-regulated kinase 1/2 pathway in neurological diseases: A potential therapeutic target (Review).Int J Mol Med. 2017;39:1338–46. [DOI] [PubMed] [PMC]
Chung YH, Joo KM, Lim HC, Cho MH, Kim D, Lee WB, et al. Immunohistochemical study on the distribution of phosphorylated extracellular signal-regulated kinase (ERK) in the central nervous system of SOD1G93A transgenic mice.Brain Res. 2005;1050:203–9. [DOI] [PubMed]
Ayala V, Granado-Serrano AB, Cacabelos D, Naudí A, Ilieva EV, Boada J, et al. Cell stress induces TDP-43 pathological changes associated with ERK1/2 dysfunction: implications in ALS.Acta Neuropathol. 2011;122:259–70. [DOI] [PubMed]
Xia Q, Hu Q, Wang H, Yang H, Gao F, Ren H, et al. Induction of COX-2-PGE2 synthesis by activation of the MAPK/ERK pathway contributes to neuronal death triggered by TDP-43-depleted microglia.Cell Death Dis. 2015;6:e1702. [DOI] [PubMed] [PMC]
Apolloni S, Parisi C, Pesaresi MG, Rossi S, Carrì MT, Cozzolino M, et al. The NADPH oxidase pathway is dysregulated by the P2X7 receptor in the SOD1-G93A microglia model of amyotrophic lateral sclerosis.J Immunol. 2013;190:5187–95. [DOI] [PubMed]
Apostol BL, Illes K, Pallos J, Bodai L, Wu J, Strand A, et al. Mutant huntingtin alters MAPK signaling pathways in PC12 and striatal cells: ERK1/2 protects against mutant huntingtin-associated toxicity.Hum Mol Genet. 2006;15:273–85. [DOI] [PubMed]
Varma H, Cheng R, Voisine C, Hart AC, Stockwell BR. Inhibitors of metabolism rescue cell death in Huntington’s disease models.Proc Natl Acad Sci U S A. 2007;104:14525–30. [DOI] [PubMed] [PMC]
Einat H, Yuan P, Gould TD, Li J, Du J, Zhang L, et al. The role of the extracellular signal-regulated kinase signaling pathway in mood modulation.J Neurosci. 2003;23:7311–6. [DOI] [PubMed] [PMC]
Réus GZ, Vieira FG, Abelaira HM, Michels M, Tomaz DB, Santos MABd, et al. MAPK signaling correlates with the antidepressant effects of ketamine.J Psychiatr Res. 2014;55:15–21. [DOI] [PubMed]
Todorovic C, Sherrin T, Pitts M, Hippel C, Rayner M, Spiess J. Suppression of the MEK/ERK signaling pathway reverses depression-like behaviors of CRF2-deficient mice.Neuropsychopharmacology. 2009;34:1416–26. [DOI] [PubMed] [PMC]
Qi X, Lin W, Li J, Li H, Wang W, Wang D, et al. Fluoxetine increases the activity of the ERK-CREB signal system and alleviates the depressive-like behavior in rats exposed to chronic forced swim stress.Neurobiol Dis. 2008;31:278–85. [DOI] [PubMed]
First M, Gil-Ad I, Taler M, Tarasenko I, Novak N, Weizman A. The effects of fluoxetine treatment in a chronic mild stress rat model on depression-related behavior, brain neurotrophins and ERK expression.J Mol Neurosci. 2011;45:246–55. [DOI] [PubMed]
Wang JQ, Tang Q, Parelkar NK, Liu Z, Samdani S, Choe ES, et al. Glutamate signaling to Ras-MAPK in striatal neurons: mechanisms for inducible gene expression and plasticity.Mol Neurobiol. 2004;29:1–14. [DOI] [PubMed]
Xing J, Ginty DD, Greenberg ME. Coupling of the RAS-MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase.Science. 1996;273:959–63. [DOI] [PubMed]
Glazova MV, Nikitina LS, Hudik KA, Kirillova OD, Dorofeeva NA, Korotkov AA, et al. Inhibition of ERK1/2 signaling prevents epileptiform behavior in rats prone to audiogenic seizures.J Neurochem. 2015;132:218–29. [DOI] [PubMed]
Stratton KR, Worley PF, Litz JS, Parsons SJ, Huganir RL, Baraban JM. Electroconvulsive treatment induces a rapid and transient increase in tyrosine phosphorylation of a 40-kilodalton protein associated with microtubule-associated protein 2 kinase activity.J Neurochem. 1991;56:147–52. [DOI] [PubMed]
Sayas CL, Ávila J. GSK-3 and Tau: A Key Duet in Alzheimer’s Disease.Cells. 2021;10:721. [DOI] [PubMed] [PMC]
Hanger DP, Hughes K, Woodgett JR, Brion JP, Anderton BH. Glycogen synthase kinase-3 induces Alzheimer’s disease-like phosphorylation of tau: generation of paired helical filament epitopes and neuronal localisation of the kinase.Neurosci Lett. 1992;147:58–62. [DOI] [PubMed]
Takashima A. GSK-3 is essential in the pathogenesis of Alzheimer’s disease.J Alzheimers Dis. 2006;9:309–17. [DOI] [PubMed]
Jaworski T, Dewachter I, Seymour CM, Borghgraef P, Devijver H, Kügler S, et al. Alzheimer’s disease: old problem, new views from transgenic and viral models.Biochim Biophys Acta. 2010;1802:808–18. [DOI] [PubMed]
Muyllaert D, Terwel D, Borghgraef P, Devijver H, Dewachter I, Leuven FV. Transgenic mouse models for Alzheimer’s disease: the role of GSK-3β in combined amyloid and tau-pathology.Rev Neurol (Paris). 2006;162:903–7. [DOI] [PubMed]
Credle JJ, George JL, Wills J, Duka V, Shah K, Lee Y, et al. GSK-3β dysregulation contributes to parkinson's-like pathophysiology with associated region-specific phosphorylation and accumulation of tau and α-synuclein.Cell Death Differ. 2015;22:838–51. [DOI] [PubMed] [PMC]
Yang W, Leystra-Lantz C, Strong MJ. Upregulation of GSK3β expression in frontal and temporal cortex in ALS with cognitive impairment (ALSci).Brain Res. 2008;1196:131–9. [DOI] [PubMed]
Law AJ, Wang Y, Sei Y, O'Donnell P, Piantadosi P, Papaleo F, et al. Neuregulin 1-ErbB4-PI3K signaling in schizophrenia and phosphoinositide 3-kinase-p110δ inhibition as a potential therapeutic strategy.Proc Natl Acad Sci U S A. 2012;109:12165–70. [DOI] [PubMed] [PMC]
Desrivières S, Krause K, Dyer A, Frank J, Blomeyer D, Lathrop M, et al. Nucleotide sequence variation within the PI3K p85 alpha gene associates with alcohol risk drinking behaviour in adolescents.PLoS One. 2008;3:e1769. [DOI] [PubMed] [PMC]
Emamian ES, Hall D, Birnbaum MJ, Karayiorgou M, Gogos JA. Convergent evidence for impaired AKT1-GSK3β signaling in schizophrenia.Nat Genet. 2004;36:131–7. [DOI] [PubMed]
Xu M, Xing Q, Zheng Y, Li S, Gao J, He G, et al. Association of AKT1 gene polymorphisms with risk of schizophrenia and with response to antipsychotics in the Chinese population.J Clin Psychiatry. 2007;68:1358–67. [DOI] [PubMed]
Thiselton DL, Vladimirov VI, Kuo P, McClay J, Wormley B, Fanous A, et al. AKT1 is associated with schizophrenia across multiple symptom dimensions in the Irish study of high density schizophrenia families.Biol Psychiatry. 2008;63:449–57. [DOI] [PubMed] [PMC]
Leibrock C, Ackermann TF, Hierlmeier M, Lang F, Borgwardt S, Lang UE. Akt2 deficiency is associated with anxiety and depressive behavior in mice.Cell Physiol Biochem. 2013;32:766–77. [DOI] [PubMed]
Li G, Anderson RE, Tomita H, Adler R, Liu X, Zack DJ, et al. Nonredundant role of Akt2 for neuroprotection of rod photoreceptor cells from light-induced cell death.J Neurosci. 2007;27:203–11. [DOI] [PubMed] [PMC]
Bergeron Y, Bureau G, Laurier-Laurin M, Asselin E, Massicotte G, Cyr M. Genetic Deletion of Akt3 Induces an Endophenotype Reminiscent of Psychiatric Manifestations in Mice.Front Mol Neurosci. 2017;10:102. [DOI] [PubMed] [PMC]
Howell KR, Floyd K, Law AJ. PKBγ/AKT3 loss-of-function causes learning and memory deficits and deregulation of AKT/mTORC2 signaling: Relevance for schizophrenia.PLoS One. 2017;12:e0175993. [DOI] [PubMed] [PMC]
Rivière J, Mirzaa GM, O’Roak BJ, Beddaoui M, Alcantara D, Conway RL, et al. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes.Nat Genet. 2012;44:934–40. [DOI] [PubMed] [PMC]
Tang H, Shen N, Jin H, Liu D, Miao X, Zhu L. GSK-3β polymorphism discriminates bipolar disorder and schizophrenia: a systematic meta-analysis.Mol Neurobiol. 2013;48:404–11. [DOI] [PubMed]
Valencia A, Reeves PB, Sapp E, Li X, Alexander J, Kegel KB, et al. Mutant huntingtin and glycogen synthase kinase 3-β accumulate in neuronal lipid rafts of a presymptomatic knock-in mouse model of Huntington’s disease.J Neurosci Res. 2010;88:179–90. [DOI] [PubMed]
Muneer A. Wnt and GSK3 Signaling Pathways in Bipolar Disorder: Clinical and Therapeutic Implications.Clin Psychopharmacol Neurosci. 2017;15:100–14. [DOI] [PubMed] [PMC]
Scala F, Nenov MN, Crofton EJ, Singh AK, Folorunso O, Zhang Y, et al. Environmental Enrichment and Social Isolation Mediate Neuroplasticity of Medium Spiny Neurons through the GSK3 Pathway.Cell Rep. 2018;23:555–67. [DOI] [PubMed] [PMC]
James TF, Nenov MN, Wildburger NC, Lichti CF, Luisi J, Vergara F, et al. The Nav1.2 channel is regulated by GSK3.Biochim Biophys Acta. 2015;1850:832–44. [DOI] [PubMed] [PMC]
Scala F, Fusco S, Ripoli C, Piacentini R, Puma DDL, Spinelli M, et al. Intraneuronal Aβ accumulation induces hippocampal neuron hyperexcitability through A-type K+ current inhibition mediated by activation of caspases and GSK-3.Neurobiol Aging. 2015;36:886–900. [DOI] [PubMed] [PMC]
Zhu L, Liu D, Hu J, Cheng J, Wang S, Wang Q, et al. GSK-3β Inhibits Presynaptic Vesicle Exocytosis by Phosphorylating P/Q-Type Calcium Channel and Interrupting SNARE Complex Formation.J Neurosci. 2010;30:3624–33. [DOI] [PubMed] [PMC]
Rakhade SN, Zhou C, Aujla PK, Fishman R, Sucher NJ, Jensen FE. Early alterations of AMPA receptors mediate synaptic potentiation induced by neonatal seizures.J Neurosci. 2008;28:7979–90. [DOI] [PubMed] [PMC]
Chen P, Gu Z, Liu W, Yan Z. Glycogen synthase kinase 3 regulates N-methyl-D-aspartate receptor channel trafficking and function in cortical neurons.Mol Pharmacol. 2007;72:40–51. [DOI] [PubMed]
Tyagarajan SK, Ghosh H, Yévenes GE, Nikonenko I, Ebeling C, Schwerdel C, et al. Regulation of GABAergic synapse formation and plasticity by GSK3β-dependent phosphorylation of gephyrin.Proc Natl Acad Sci U S A. 2011;108:379–84. [DOI] [PubMed] [PMC]
Jaworski T. Control of neuronal excitability by GSK-3beta: Epilepsy and beyond.Biochim Biophys Acta Mol Cell Res. 2020;1867:118745. [DOI] [PubMed]
Costa-Mattioli M, Monteggia LM. mTOR complexes in neurodevelopmental and neuropsychiatric disorders.Nat Neurosci. 2013;16:1537–43. [DOI] [PubMed]
Huber KM, Klann E, Costa-Mattioli M, Zukin RS. Dysregulation of Mammalian Target of Rapamycin Signaling in Mouse Models of Autism.J Neurosci. 2015;35:13836–42. [DOI] [PubMed] [PMC]
Lipton JO, Sahin M. The neurology of mTOR.Neuron. 2014;84:275–91. [DOI] [PubMed] [PMC]
Xu Y, Liu C, Chen S, Ye Y, Guo M, Ren Q, et al. Activation of AMPK and inactivation of Akt result in suppression of mTOR-mediated S6K1 and 4E-BP1 pathways leading to neuronal cell death in in vitro models of Parkinson's disease.Cell Signal. 2014;26:1680–9. [DOI] [PubMed] [PMC]
Zhou Q, Liu C, Liu W, Zhang H, Zhang R, Liu J, et al. Rotenone induction of hydrogen peroxide inhibits mTOR-mediated S6K1 and 4E-BP1/eIF4E pathways, leading to neuronal apoptosis.Toxicol Sci. 2015;143:81–96. [DOI] [PubMed] [PMC]
O’Donnell A, Faivre S, 3rd HAB, Rea D, Papadimitrakopoulou V, Shand N, et al. Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors.J Clin Oncol. 2008;26:1588–95. [DOI] [PubMed]
Yu K, Shi C, Toral-Barza L, Lucas J, Shor B, Kim JE, et al. Beyond rapalog therapy: preclinical pharmacology and antitumor activity of WYE-125132, an ATP-competitive and specific inhibitor of mTORC1 and mTORC2.Cancer Res. 2010;70:621–31. [DOI] [PubMed]
Knafo S, Esteban JA. PTEN: Local and Global Modulation of Neuronal Function in Health and Disease.Trends Neurosci. 2017;40:83–91. [DOI] [PubMed]
Winden KD, Ebrahimi-Fakhari D, Sahin M. Abnormal mTOR Activation in Autism.Annu Rev Neurosci. 2018;41:1–23. [DOI] [PubMed]
Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex.Science. 2005;307:1098–101. [DOI] [PubMed]
Chen C, Sgritta M, Mays J, Zhou H, Lucero R, Park J, et al. Therapeutic inhibition of mTORC2 rescues the behavioral and neurophysiological abnormalities associated with Pten-deficiency.Nat Med. 2019;25:1684–90. [DOI] [PubMed] [PMC]
García-Martínez JM, Alessi DR. mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1).Biochem J. 2008;416:375–85. [DOI] [PubMed]
Lau A, Tymianski M. Glutamate receptors, neurotoxicity and neurodegeneration.Pflugers Arch. 2010;460:525–42. [DOI] [PubMed]
Lang UE, Puls I, Muller DJ, Strutz-Seebohm N, Gallinat J. Molecular mechanisms of schizophrenia.Cell Physiol Biochem. 2007;20:687–702. [DOI] [PubMed]
Lang F, Böhmer C, Palmada M, Seebohm G, Strutz-Seebohm N, Vallon V. (Patho)physiological significance of the serum- and glucocorticoid-inducible kinase isoforms.Physiol Rev. 2006;86:1151–78. [DOI] [PubMed]
Sakai R, Irie Y, Murata T, Ishige A, Anjiki N, Watanabe K. Toki-to protects dopaminergic neurons in the substantia nigra from neurotoxicity of MPTP in mice.Phytother Res. 2007;21:868–73. [DOI] [PubMed]
Jang H, Park Y, Jang J. Serum and glucocorticoid-regulated kinase 1: Structure, biological functions, and its inhibitors.Front Pharmacol. 2022;13:1036844. [DOI] [PubMed] [PMC]
Ittner AA, Gladbach A, Bertz J, Suh LS, Ittner LM. p38 MAP kinase-mediated NMDA receptor-dependent suppression of hippocampal hypersynchronicity in a mouse model of Alzheimer's disease.Acta Neuropathol Commun. 2014;2:149. [DOI] [PubMed] [PMC]
Sun A, Liu M, Nguyen XV, Bing G. P38 MAP kinase is activated at early stages in Alzheimer’s disease brain.Exp Neurol. 2003;183:394–405. [DOI] [PubMed]
Li S, Jin M, Koeglsperger T, Shepardson NE, Shankar GM, Selkoe DJ. Soluble Aβ oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors.J Neurosci. 2011;31:6627–38. [DOI] [PubMed] [PMC]
Colié S, Sarroca S, Palenzuela R, Garcia I, Matheu A, Corpas R, et al. Neuronal p38α mediates synaptic and cognitive dysfunction in an Alzheimer’s mouse model by controlling β-amyloid production.Sci Rep. 2017;7:45306. [DOI] [PubMed] [PMC]
Origlia N, Righi M, Capsoni S, Cattaneo A, Fang F, Stern DM, et al. Receptor for Advanced Glycation End Product-Dependent Activation of p38 Mitogen-Activated Protein Kinase Contributes to Amyloid-β-Mediated Cortical Synaptic Dysfunction.J Neurosci. 2008;28:3521–30. [DOI] [PubMed] [PMC]
Maphis N, Jiang S, Xu G, Kokiko-Cochran ON, Roy SM, Eldik LJV, et al. Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology.Alzheimers Res Ther. 2016;8:54. [DOI] [PubMed] [PMC]
Schnöder L, Hao W, Qin Y, Liu S, Tomic I, Liu X, et al. Deficiency of Neuronal p38α MAPK Attenuates Amyloid Pathology in Alzheimer Disease Mouse and Cell Models through Facilitating Lysosomal Degradation of BACE1.J Biol Chem. 2016;291:2067–79. [DOI] [PubMed] [PMC]
Ittner A, Ittner LM. Dendritic Tau in Alzheimer’s Disease.Neuron. 2018;99:13–27. [DOI] [PubMed]
Ittner A, Chua SW, Bertz J, Volkerling A, Hoven Jvd, Gladbach A, et al. Site-specific phosphorylation of tau inhibits amyloid-β toxicity in Alzheimer’s mice.Science. 2016;354:904–8. [DOI] [PubMed]
Sama RRK, Fallini C, Gatto R, McKeon JE, Song Y, Rotunno MS, et al. ALS-linked FUS exerts a gain of toxic function involving aberrant p38 MAPK activation.Sci Rep. 2017;7:115. [DOI] [PubMed] [PMC]
Lee JK, Shin JH, Hwang SG, Gwag BJ, McKee AC, Lee J, et al. MST1 functions as a key modulator of neurodegeneration in a mouse model of ALS.Proc Natl Acad Sci U S A. 2013;110:12066–71. [DOI] [PubMed] [PMC]
Krieger C, Hu JH, Pelech S. Aberrant protein kinases and phosphoproteins in amyotrophic lateral sclerosis.Trends Pharmacol Sci. 2003;24:535–41. [DOI] [PubMed]
Dewil M, Cruz VFd, Bosch LVD, Robberecht W. Inhibition of p38 mitogen activated protein kinase activation and mutant SOD1G93A-induced motor neuron death.Neurobiol Dis. 2007;26:332–41. [DOI] [PubMed]
Karunakaran S, Saeed U, Mishra M, Valli RK, Joshi SD, Meka DP, et al. Selective activation of p38 mitogen-activated protein kinase in dopaminergic neurons of substantia nigra leads to nuclear translocation of p53 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice.J Neurosci. 2008;28:12500–9. [DOI] [PubMed] [PMC]
Ray A, Sehgal N, Karunakaran S, Rangarajan G, Ravindranath V. MPTP activates ASK1-p38 MAPK signaling pathway through TNF-dependent Trx1 oxidation in parkinsonism mouse model.Free Radic Biol Med. 2015;87:312–25. [DOI] [PubMed]
Chang A, Li PP, Warsh JJ. Altered cAMP-dependent protein kinase subunit immunolabeling in post-mortem brain from patients with bipolar affective disorder.J Neurochem. 2003;84:781–91. [DOI] [PubMed]
Akin D, Manier DH, Sanders-Bush E, Shelton RC. Signal transduction abnormalities in melancholic depression.Int J Neuropsychopharmacol. 2005;8:5–16. [DOI] [PubMed]
Dwivedi Y, Pandey GN. Adenylyl cyclase-cyclicAMP signaling in mood disorders: role of the crucial phosphorylating enzyme protein kinase A.Neuropsychiatr Dis Treat. 2008;4:161–76. [DOI] [PubMed] [PMC]
Plattner F, Hayashi K, Hernández A, Benavides DR, Tassin TC, Tan C, et al. The role of ventral striatal cAMP signaling in stress-induced behaviors.Nat Neurosci. 2015;18:1094–100. [DOI] [PubMed] [PMC]
Sepp M, Vihma H, Nurm K, Urb M, Page SC, Roots K, et al. The Intellectual Disability and Schizophrenia Associated Transcription Factor TCF4 Is Regulated by Neuronal Activity and Protein Kinase A.J Neurosci. 2017;37:10516–27. [DOI] [PubMed] [PMC]
Fjodorova M, Noakes Z, Fuente DCDL, Errington AC, Li M. Dysfunction of cAMP-Protein Kinase A-Calcium Signaling Axis in Striatal Medium Spiny Neurons: A Role in Schizophrenia and Huntington’s Disease Neuropathology.Biol Psychiatry Glob Open Sci. 2022;3:418–29. [DOI] [PubMed] [PMC]
Vitolo OV, Sant’Angelo A, Costanzo V, Battaglia F, Arancio O, Shelanski M. Amyloid β-peptide inhibition of the PKA/CREB pathway and long-term potentiation: Reversibility by drugs that enhance cAMP signaling.Proc Natl Acad Sci U S A. 2002;99:13217–21. [DOI] [PubMed] [PMC]
Banerjee TD, Reihl K, Swain M, Torres M, Dagda RK. Mitochondrial PKA Is Neuroprotective in a Cell Culture Model of Alzheimer's Disease.Mol Neurobiol. 2021;58:3071–83. [DOI] [PubMed] [PMC]
Alkon DL, Sun M, Nelson TJ. PKC signaling deficits: a mechanistic hypothesis for the origins of Alzheimer's disease.Trends Pharmacol Sci. 2007;28:51–60. [DOI] [PubMed]
Chen J, Lin HH, Kim K, Lin A, Ou JJ, Ann DK. PKCδ signaling: A dual role in regulating hypoxic stress-induced autophagy and apoptosis.Autophagy. 2009;5:244–6. [DOI] [PubMed] [PMC]
Du Y, Zhao Y, Li C, Zheng Q, Tian J, Li Z, et al. Inhibition of PKCδ reduces amyloid-β levels and reverses Alzheimer disease phenotypes.J Exp Med. 2018;215:1665–77. [DOI] [PubMed] [PMC]
Benowitz LI, Routtenberg A. GAP-43: an intrinsic determinant of neuronal development and plasticity.Trends Neurosci. 1997;20:84–91. [DOI] [PubMed]
He Q, Dent EW, Meiri KF. Modulation of actin filament behavior by GAP-43 (neuromodulin) is dependent on the phosphorylation status of serine 41, the protein kinase C site.J Neurosci. 1997;17:3515–24. [DOI] [PubMed] [PMC]
Su R, Han Z, Fan J, Zhang Y. A possible role of myristoylated alanine-rich C kinase substrate in endocytic pathway of Alzheimer's disease.Neurosci Bull. 2010;26:338–44. [DOI] [PubMed] [PMC]
Thelen M, Rosen A, Nairn AC, Aderem A. Regulation by phosphorylation of reversible association of a myristoylated protein kinase C substrate with the plasma membrane.Nature. 1991;351:320–2. [DOI] [PubMed]
Chung HJ, Xia J, Scannevin RH, Zhang X, Huganir RL. Phosphorylation of the AMPA receptor subunit GluR2 differentially regulates its interaction with PDZ domain-containing proteins.J Neurosci. 2000;20:7258–67. [DOI] [PubMed] [PMC]
Perez JL, Khatri L, Chang C, Srivastava S, Osten P, Ziff EB. PICK1 Targets Activated Protein Kinase Cα to AMPA Receptor Clusters in Spines of Hippocampal Neurons and Reduces Surface Levels of the AMPA-Type Glutamate Receptor Subunit 2.J Neurosci. 2001;21:5417–28. [DOI] [PubMed] [PMC]
Iyer DN, Faruq O, Zhang L, Rastgoo N, Liu A, Chang H. Pathophysiological roles of myristoylated alanine-rich C-kinase substrate (MARCKS) in hematological malignancies.Biomark Res. 2021;9:34. [DOI] [PubMed] [PMC]
Wong MMK, Hoekstra SD, Vowles J, Watson LM, Fuller G, Németh AH, et al. Neurodegeneration in SCA14 is associated with increased PKCγ kinase activity, mislocalization and aggregation.Acta Neuropathol Commun. 2018;6:99. [DOI] [PubMed] [PMC]
Birnbaum SG, Yuan PX, Wang M, Vijayraghavan S, Bloom AK, Davis DJ, et al. Protein kinase C overactivity impairs prefrontal cortical regulation of working memory.Science. 2004;306:882–4. [DOI] [PubMed]
Yildiz A, Aydin B, Gökmen N, Yurt A, Cohen B, Keskinoglu P, et al. Antimanic Treatment With Tamoxifen Affects Brain Chemistry: A Double-Blind, Placebo-Controlled Proton Magnetic Resonance Spectroscopy Study.Biol Psychiatry Cogn Neurosci Neuroimaging. 2016;1:125–31. [DOI] [PubMed] [PMC]
Wegner KW, Saleh D, Degterev A. Complex Pathologic Roles of RIPK1 and RIPK3: Moving Beyond Necroptosis.Trends Pharmacol Sci. 2017;38:202–25. [DOI] [PubMed] [PMC]
Petratos S, Li Q, George AJ, Hou X, Kerr ML, Unabia SE, et al. The β-amyloid protein of Alzheimer’s disease increases neuronal CRMP-2 phosphorylation by a Rho-GTP mechanism.Brain. 2008;131:90–108. [DOI] [PubMed]
Pichon CEL, Meilandt WJ, Dominguez S, Solanoy H, Lin H, Ngu H, et al. Loss of dual leucine zipper kinase signaling is protective in animal models of neurodegenerative disease.Sci Transl Med. 2017;9:eaag0394. [DOI] [PubMed]
Paisán-Ruiz C, Lewis PA, Singleton AB. LRRK2: cause, risk, and mechanism.J Parkinsons Dis. 2013;3:85–103. [DOI] [PubMed] [PMC]
Muda K, Bertinetti D, Gesellchen F, Hermann JS, Zweydorf Fv, Geerlof A, et al. Parkinson-related LRRK2 mutation R1441C/G/H impairs PKA phosphorylation of LRRK2 and disrupts its interaction with 14-3-3.Proc Natl Acad Sci U S A. 2014;111:E34–43. [DOI] [PubMed] [PMC]
Mehdi SJ, Rosas-Hernandez H, Cuevas E, Lantz SM, Barger SW, Sarkar S, et al. Protein Kinases and Parkinson’s Disease.Int J Mol Sci. 2016;17:1585. [DOI] [PubMed] [PMC]
Evangelisti C, Chiarini F, Paganelli F, Marmiroli S, Martelli AM. Crosstalks of GSK3 signaling with the mTOR network and effects on targeted therapy of cancer.Biochim Biophys Acta Mol Cell Res. 2020;1867:118635. [DOI] [PubMed]
Engmann O, Giese KP. Crosstalk between Cdk5 and GSK3β: Implications for Alzheimer’s Disease.Front Mol Neurosci. 2009;2:2. [DOI] [PubMed] [PMC]
Baumann K, Mandelkow EM, Biernat J, Piwnica-Worms H, Mandelkow E. Abnormal Alzheimer-like phosphorylation of tau-protein by cyclin-dependent kinases cdk2 and cdk5.FEBS Lett. 1993;336:417–24. [DOI] [PubMed]
Zhang X, Hernandez I, Rei D, Mair W, Laha JK, Cornwell ME, et al. Diaminothiazoles modify Tau phosphorylation and improve the tauopathy in mouse models.J Biol Chem. 2013;288:22042–56. [DOI] [PubMed] [PMC]
Zukerberg LR, Patrick GN, Nikolic M, Humbert S, Wu CL, Lanier LM, et al. Cables links Cdk5 and c-Abl and facilitates Cdk5 tyrosine phosphorylation, kinase upregulation, and neurite outgrowth.Neuron. 2000;26:633–46. [DOI] [PubMed]
Cancino GI, Arce KPd, Castro PU, Toledo EM, Bernhardi Rv, Alvarez AR. c-Abl tyrosine kinase modulates tau pathology and Cdk5 phosphorylation in AD transgenic mice.Neurobiol Aging. 2011;32:1249–61. [DOI] [PubMed]
Salcedo-Arellano MJ, Cabal-Herrera AM, Punatar RH, Clark CJ, Romney CA, Hagerman RJ. Overlapping Molecular Pathways Leading to Autism Spectrum Disorders, Fragile X Syndrome, and Targeted Treatments.Neurotherapeutics. 2021;18:265–83. [DOI] [PubMed] [PMC]
Shen M, Lv D, Liu X, Wang C. ERK/mTOR signaling may underlying the antidepressant actions of rapastinel in mice.Transl Psychiatry. 2022;12:522. [DOI] [PubMed] [PMC]
Tamagno E, Guglielmotto M, Giliberto L, Vitali A, Borghi R, Autelli R, et al. JNK and ERK1/2 pathways have a dual opposite effect on the expression of BACE1.Neurobiol Aging. 2009;30:1563–73. [DOI] [PubMed]
Brownlees J, Yates A, Bajaj NP, Davis D, Anderton BH, Leigh PN, et al. Phosphorylation of neurofilament heavy chain side-arms by stress activated protein kinase-1b/Jun N-terminal kinase-3.J Cell Sci. 2000;113 :401–7. [DOI] [PubMed]
Bendotti C, Atzori C, Piva R, Tortarolo M, Strong MJ, DeBiasi S, et al. Activated p38MAPK is a novel component of the intracellular inclusions found in human amyotrophic lateral sclerosis and mutant SOD1 transgenic mice.J Neuropathol Exp Neurol. 2004;63:113–9. [DOI] [PubMed]
Colbran RJ, Brown AM. Calcium/calmodulin-dependent protein kinase II and synaptic plasticity.Curr Opin Neurobiol. 2004;14:318–27. [DOI] [PubMed]
Heffron TP. Challenges of developing small-molecule kinase inhibitors for brain tumors and the need for emphasis on free drug levels.Neuro Oncol. 2018;20:307–12. [DOI] [PubMed] [PMC]
Wu D, Chen Q, Chen X, Han F, Chen Z, Wang Y. The blood-brain barrier: structure, regulation and drug delivery.Signal Transduct Target Ther. 2023;8:217. [DOI] [PubMed] [PMC]
Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, et al. A quantitative analysis of kinase inhibitor selectivity.Nat Biotechnol. 2008;26:127–32. [DOI] [PubMed]
Mahalmani V, Sinha S, Prakash A, Medhi B. Translational research: Bridging the gap between preclinical and clinical research.Indian J Pharmacol. 2022;54:393–6. [DOI] [PubMed] [PMC]
A PHP Error was encountered
Severity: Core Warning
Message: PHP Startup: Unable to load dynamic library '/www/server/php/72/lib/php/extensions/no-debug-non-zts-20170718/bt_safe.so' (tried: /www/server/php/72/lib/php/extensions/no-debug-non-zts-20170718/bt_safe.so (/www/server/php/72/lib/php/extensions/no-debug-non-zts-20170718/bt_safe.so: cannot open shared object file: No such file or directory), /www/server/php/72/lib/php/extensions/no-debug-non-zts-20170718//www/server/php/72/lib/php/extensions/no-debug-non-zts-20170718/bt_safe.so.so (/www/server/php/72/lib/php/extensions/no-debug-non-zts-20170718//www/server/php/72/lib/php/extensions/no-debug-non-zts-20170718/bt_safe.so.so: cannot open shared object file: No such file or directory))
