CDK5-mediated phosphorylation and autophagy of RKIP regulate neuronal death in Parkinson's disease

Wen, Zheng; Yang, Shu; Gao, Caiyun; Wang, Xuemin; Qi, Guangjian; Zhang, Pei; Li, Man; Shi, Jing; Tian, Bo

doi:10.1016/j.neurobiolaging.2014.05.034

Cited by 50 publications

(43 citation statements)

References 48 publications

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“…These results provided direct evidence that the autophagy induced by MPTP was mediated by CDK5. Consistent with previous reports, 14,46 we found that MPTP induced cell death in C6 cells in a dose-dependent manner (Fig. 2J).…”

Section: Mptp Induced Cdk5-mediated Autophagy Leading To Death Of C6supporting

confidence: 93%

“…14,55 Recent studies report that CDK5-mediated phosphorylation and autophagy of PEBP1 regulates neuronal death in PD.…”

Section: Discussionmentioning

confidence: 99%

“…14,31,46 We investigated whether CDK5 was changed during the development of the monkey PD model. We found that MPTP could induce higher CDK5 level in the monkey brain tissues, with the most striking effect in the substantia nigra region (Fig.…”

Section: Mptp Induced Autophagy In Monkey Brain Tissuesmentioning

confidence: 99%

“…[10][11][12] Activation of CDK5 requires its regulatory partner CDK5R1/p35/p25 (cyclin-dependent kinase 5, regulatory subunit 1 [p35]). 13 Accumulating evidence indicates that MPTP increases CDK5 activity 11,12 and triggers neuronal loss through phosphorylation and inhibition of PEBP1/RKIP (phosphatidylethanolamine-binding protein 1), 14 survival factor MEF2 (myocyte enhancer factor 2), 15 antioxidant enzyme PRDX2/Prx2 (peroxiredoxin 2), 16 and APEX1/Ape-1 (APEX nuclease [multifunctional DNA repair enzyme] 1). 11 Autophagy is a lysosomal degradation pathway that controls the turnover of cytoplasmic contents and organelles through the engulfment of cargo into double-membrane autophagosomes.…”

Section: Introductionmentioning

confidence: 99%

“…20,29,30 The CDK5-mediated autophagy contributes to neuronal loss in PD animal models. 14,31 Melatonin, the main secretory product of the pineal gland, can easily cross the blood-brain barrier and has plentiful neuroprotective properties such as regulating circadian rhythms and providing anti-inflammatory and neuronal protection. [32][33][34] As a naturally occurring compound, melatonin has potential effects on inhibiting autophagy through a redox-mediated scavenge of free radicals and lipid peroxidation, 35 as well as its well-known antioxidant properties.…”

Section: Introductionmentioning

confidence: 99%

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Melatonin attenuates MPTP-induced neurotoxicity via preventing CDK5-mediated autophagy and SNCA/α-synuclein aggregation

et al. 2015

Autophagy

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Keywords: autophagy, CDK5, melatonin, MPTP, SNCA, TH Abbreviations: ATG7, autophagy-related 7; BAFA1, bafilomycin A 1 ; CDK5, cyclin-dependent kinase 5; CDK5R1/p35/p25, cyclindependent kinase 5, regulatory subunit 1 (p35); DA, dopamine; DAPI, 4 0 ,6-diamidino-2-phenylindole; i.p, intraperitoneally; s.c, subcutaneously; ICV, intracerebroventricular; MAP1LC3B/LC3B, microtubule-associated protein 1 light chain 3 b; MAP2, microtube-associated protein 2; MPTP, 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine; PD, Parkinson disease; PEBP1, phosphatidylethanolamine binding protein 1; PI, propidium iodide; SNc, substantia nigra pars compacta; SNCA/a-synuclein, synuclein, a (non A4 component of amyloid precursor); TH, tyrosine hydroxylase.Autophagy is involved in the pathogenesis of neurodegenerative diseases including Parkinson disease (PD). However, little is known about the regulation of autophagy in neurodegenerative process. In this study, we characterized aberrant activation of autophagy induced by neurotoxin 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and demonstrated that melatonin has a protective effect on neurotoxicity. We found an excessive activation of autophagy in monkey brain tissues and C6 cells, induced by MPTP, which is mediated by CDK5 (cyclin-dependent kinase 5). MPTP treatment significantly reduced total dendritic length and dendritic complexity of cultured primary cortical neurons and melatonin could reverse this effect. Decreased TH (tyrosine hydroxylase)-positive cells and dendrites of dopaminergic neurons in the substantia nigra pars compacta (SNc) were observed in MPTP-treated monkeys and mice. Along with decreased TH protein level, we observed an upregulation of CDK5 and enhanced autophagic activity in the striatum of mice with MPTP injection. These changes could be salvaged by melatonin treatment or knockdown of CDK5. Importantly, melatonin or knockdown of CDK5 reduced MPTP-induced SNCA/ a-synuclein aggregation in mice, which is widely thought to trigger the pathogenesis of PD. Finally, melatonin or knockdown of CDK5 counteracted the PD phenotype in mice induced by MPTP. Our findings uncover a potent role of CDK5-mediated autophagy in the pathogenesis of PD, and suggest that control of autophagic pathways may provide an important clue for exploring potential target for novel therapeutics of PD.

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Section: Mptp Induced Cdk5-mediated Autophagy Leading To Death Of C6supporting

confidence: 93%

“…14,55 Recent studies report that CDK5-mediated phosphorylation and autophagy of PEBP1 regulates neuronal death in PD.…”

Section: Discussionmentioning

confidence: 99%

Section: Mptp Induced Autophagy In Monkey Brain Tissuesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Melatonin attenuates MPTP-induced neurotoxicity via preventing CDK5-mediated autophagy and SNCA/α-synuclein aggregation

et al. 2015

Autophagy

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Fluorescent Biosensor of CDK5 Kinase Activity in Glioblastoma Cell Extracts and Living Cells

Peyressatre

Laure

Pellerano

et al. 2020

Biotechnology Journal

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CDK5 plays a major role in neuronal functions, and is hyperactivated in neurodegenerative pathologies as well as in glioblastoma and neuroblastoma. Although this kinase constitutes an established biomarker and pharmacological target, there are few means of probing its activity in cell extracts or in living cells. To this aim a fluorescent peptide reporter of CDK5 kinase activity, derived from a library of CDK5‐specific substrates, is engineered and its ability to respond to recombinant CDK5/p25 is established and CDK5 activity in glioblastoma cell extracts is reported on through sensitive changes in fluorescence intensity. A cell‐penetrating variant of this biosensor which can be implemented to image CDK5 activation dynamics in space and in time is further implemented. This original biosensor constitutes a potent tool for quantifying differences in CDK5 activity following treatment with selective inhibitors and for monitoring CDK5 activation, following inhibition or stimulation, in a physiologically relevant environment. As such it offers attractive opportunities to develop a diagnostic assay for neuronal pathologies associated with hyperactivated CDK5, as well as a companion assay to evaluate response to new therapies targeting this kinase.

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Understanding perspectives of signalling mechanisms regulating PEBP1 function

Rajkumar

Nichita

Anoor

et al. 2016

Cell Biochemistry & Function

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CDK5-mediated phosphorylation and autophagy of RKIP regulate neuronal death in Parkinson's disease

Cited by 50 publications

References 48 publications

Melatonin attenuates MPTP-induced neurotoxicity via preventing CDK5-mediated autophagy and SNCA/α-synuclein aggregation

Melatonin attenuates MPTP-induced neurotoxicity via preventing CDK5-mediated autophagy and SNCA/α-synuclein aggregation

Fluorescent Biosensor of CDK5 Kinase Activity in Glioblastoma Cell Extracts and Living Cells

Understanding perspectives of signalling mechanisms regulating PEBP1 function

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