The role of Cdk5-mediated apurinic/apyrimidinic endonuclease 1 phosphorylation in neuronal death

Huang, Emma; Qu, Dianbo; Zhang, Yi; Venderová, Kateřina; Haque, M. Emdadul; Rousseaux, Maxime W.C.; Slack, Ruth S.; Woulfe, John; Park, David

doi:10.1038/ncb2058

Cited by 113 publications

(114 citation statements)

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“…For siRNA transfection, neurons were transfected with 30 pmol/well (24-well plate) siRNA to mouse bag2, pink1, or parkin plus 30 pmol/well of control siRNA to 60 pmol siRNA in total. For co-transfection of siRNAs, neurons were transfected with 30 pmol/well of each using Lipofectamine 2000 as described previously (32). 24 h after transfection, the neurons were treated with 20 M MPP ϩ for 48 h. The 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was carried out.…”

Section: Methodsmentioning

confidence: 99%

BAG2 Gene-mediated Regulation of PINK1 Protein Is Critical for Mitochondrial Translocation of PARKIN and Neuronal Survival

Hage

Don-Carolis

et al. 2015

Journal of Biological Chemistry

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Emerging evidence has demonstrated a growing genetic component in Parkinson disease (PD). For instance, loss-of-function mutations in PINK1 or PARKIN can cause autosomal recessive PD. Recently, PINK1 and PARKIN have been implicated in the same signaling pathway to regulate mitochondrial clearance through recruitment of PARKIN by stabilization of PINK1 on the outer membrane of depolarized mitochondria. The precise mechanisms that govern this process remain enigmatic. In this study, we identify Bcl2-associated athanogene 2 (BAG2) as a factor that promotes mitophagy. BAG2 inhibits PINK1 degradation by blocking the ubiquitination pathway. Stabilization of PINK1 by BAG2 triggers PARKIN-mediated mitophagy and protects neurons against 1-methyl-4-phenylpyridinium-induced oxidative stress in an in vitro cell model of PD. Collectively, our findings support the notion that BAG2 is an upstream regulator of the PINK1/PARKIN signaling pathway. Parkinson disease (PD)2 is the second most common neurodegenerative disorder, characterized by selective loss of the pigmented dopaminergic neurons of the substantia nigra pars compacta (1). Although most PD cases are sporadic in nature (2), mutations in several genes have been linked to familial forms of PD (reviewed in Ref.3). Indeed, these familial genes serve as important vehicles to study the potential mechanisms of pathogenesis in PD. In this regard, increasing evidence suggests that mitochondrial dysfunction may play a critical role in both the inherited and sporadic forms of PD, although the precise role of mitochondrial dysfunction in PD is unclear (4). Recently, two familial recessive PD genes, PTEN-induced putative kinase 1 (PINK1), a mitochondrially localized serine/threonine kinase gene, and PARKIN, an E3 ubiquitin ligase gene, have been identified as acting along similar pathways in regulating mitochondrial quality control in mammalian systems (5-8). These findings are supported by genetic studies in Drosophila models of PD that show that PARKIN and PINK1 function in a common pathway, with PARKIN being a downstream player of PINK1 (9 -11). A third recessive PD gene, DJ-1, associated with the regulation of oxidative stress, also regulates PINK1/PARKIN-mediated control of mitochondrial health (12).PINK1 is normally shuttled to the inner mitochondrial membrane where it is processed by multiple proteases (13). The endogenous role of PINK1 at this site is unknown. However, PINK1-deficient cells display altered calcium homeostasis at the mitochondria as well as altered mitochondrial function (14). Processed PINK1 at the inner mitochondrial membrane has also been proposed to be shuttled to the cytosol, where it is degraded by the proteasome (15). However, under conditions of mitochondrial stress such as treatment with the mitochondrial uncoupler carbonyl cyanide p-chlorophenylhydrazone (CCCP) or with the complex I inhibitor 1-methyl-4-phenylpyridinium (MPP ϩ ), PINK1 can also regulate mitophagy in a PARKIN-dependent fashion (12, 16 -19). The framework by which this mitochondrial ...

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Section: Methodsmentioning

confidence: 99%

BAG2 Gene-mediated Regulation of PINK1 Protein Is Critical for Mitochondrial Translocation of PARKIN and Neuronal Survival

Hage

Don-Carolis

et al. 2015

Journal of Biological Chemistry

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“…With regard to PD, one recent study involving 60 case subjects and 108 normal controls found that the D148E variant of APE1 had a positive association as a risk factor for the disease (59), although it was acknowledged by the authors that more extensive follow-up experiments are needed to validate this observation. Finally, Huang et al (84), in addition to confirming the importance of APE1 in neuronal cell viability, possibly in a mechanism involving Cdk5 phosphorylation of residue T232 (in the mouse protein, T233 in the human protein), which inactivates the enzyme's AP endonuclease activity (see Table 1), detected an increase in the T233-phosphorylated form of APE1 in post-mortem brain samples from PD and AD patients, uncovering a possible molecular connection between APE1 inactivation and neurodegenerative disease.…”

Section: Neuropathologymentioning

confidence: 99%

Human Apurinic/Apyrimidinic Endonuclease 1

2014

Antioxidants & Redox Signaling

228

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Significance: Human apurinic/apyrimidinic endonuclease 1 (APE1, also known as REF-1) was isolated based on its ability to cleave at AP sites in DNA or activate the DNA binding activity of certain transcription factors. We review herein topics related to this multi-functional DNA repair and stress-response protein. Recent Advances: APE1 displays homology to Escherichia coli exonuclease III and is a member of the divalent metal-dependent a/b fold-containing phosphoesterase superfamily of enzymes. APE1 has acquired distinct active site and loop elements that dictate substrate selectivity, and a unique N-terminus which at minimum imparts nuclear targeting and interaction specificity. Additional activities ascribed to APE1 include 3¢-5¢ exonuclease, 3¢-repair diesterase, nucleotide incision repair, damaged or site-specific RNA cleavage, and multiple transcription regulatory roles. Critical Issues: APE1 is essential for mouse embryogenesis and contributes to cell viability in a genetic background-dependent manner. Haploinsufficient APE1 +/ -mice exhibit reduced survival, increased cancer formation, and cellular/tissue hyper-sensitivity to oxidative stress, supporting the notion that impaired APE1 function associates with disease susceptibility. Although abnormal APE1 expression/localization has been seen in cancer and neuropathologies, and impaired-function variants have been described, a causal link between an APE1 defect and human disease remains elusive. Future Directions: Ongoing efforts aim at delineating the biological role(s) of the different APE1 activities, as well as the regulatory mechanisms for its intra-cellular distribution and participation in diverse molecular pathways. The determination of whether APE1 defects contribute to human disease, particularly pathologies that involve oxidative stress, and whether APE1 small-molecule regulators have clinical utility, is central to future investigations. Antioxid. Redox Signal. 20,

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“…[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%

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

et al. 2015

Autophagy

110

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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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The role of Cdk5-mediated apurinic/apyrimidinic endonuclease 1 phosphorylation in neuronal death

Cited by 113 publications

References 51 publications

BAG2 Gene-mediated Regulation of PINK1 Protein Is Critical for Mitochondrial Translocation of PARKIN and Neuronal Survival

BAG2 Gene-mediated Regulation of PINK1 Protein Is Critical for Mitochondrial Translocation of PARKIN and Neuronal Survival

Human Apurinic/Apyrimidinic Endonuclease 1

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

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