Effect of the overexpression of wild‐type or mutant α‐synuclein on cell susceptibility to insult

Lee, MoonHee; Hyun, Dong Hoon; Halliwell, Barry; Jenner, Peter

doi:10.1046/j.1471-4159.2001.00149.x

Cited by 226 publications

(172 citation statements)

References 53 publications

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“…These results are strikingly similar to those recently demonstrated for another protein involved in PD, namely ␣-synuclein. Wildtype but not mutant ␣-synuclein also limited cell death triggered by serum withdrawal (14).…”

Section: Discussionmentioning

confidence: 92%

Wild-type PINK1 Prevents Basal and Induced Neuronal Apoptosis, a Protective Effect Abrogated by Parkinson Disease-related Mutations

Petit

Kawarai²,

Paitel³

et al. 2005

Journal of Biological Chemistry

297

243

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Mutations in the PTEN-induced kinase 1 (PINK1) gene have recently been implicated in autosomal recessive early onset Parkinson Disease (1, 2). To investigate the role of PINK1 in neurodegeneration, we designed human and murine neuronal cell lines expressing either wild-type PINK1 or PINK1 bearing a mutation associated with Parkinson Disease. We show that under basal and staurosporine-induced conditions, the number of terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL)-positive cells was lower in wild-type PINK1 expressing SH-SY5Y cells than in mock-transfected cells. This phenotype was due to a PINK1-mediated reduction in cytochrome c release from mitochondria, which prevents subsequent caspase-3 activation. We show that overexpression of wild-type PINK1 strongly reduced both basal and staurosporine-induced caspase 3 activity. Overexpression of wild-type PINK1 also reduced the levels of cleaved caspase-9, caspase-3, caspase-7, and activated poly(ADP-ribose) polymerase under both basal and staurosporine-induced conditions. In contrast, Parkinson disease-related mutations and a kinase-inactive mutation in PINK1 abrogated the protective effect of PINK1. Together, these results suggest that PINK1 reduces the basal neuronal pro-apoptotic activity and protects neurons from staurosporine-induced apoptosis. Loss of this protective function may therefore underlie the degeneration of nigral dopaminergic neurons in patients with PINK1 mutations. Parkinson disease (PD)2 is the most common neurodegenerative movement disorder, affecting ϳ1% of the population by age 65 years (3, 4). It is characterized by the predominant degeneration of midbrain dopaminergic neurons. Although most patients with PD are sporadic, familial cases represent ϳ10% of all diagnoses. To date, six genes responsible for inherited forms of PD have been identified. Mutations in the ␣-synuclein (5), LRRK2 (leucine-rich repeat kinase 2) and UCH-L1 (ubiquitin C-terminal esterase L1) genes cause dominant forms of familial PD. In contrast, mutations in parkin (6), DJ-1 (7,8), and the newly identified PTEN (phosphatase and tensin homologue on chromosome 10)-induced kinase 1 (PINK1) (1, 2) are responsible for recessive forms of familial PD.PINK1 encodes a highly conserved, 581-amino acid, putative serinethreonine protein kinase and is a member of a small family of novel kinases including CLIK1 (CLP-36 interacting kinase)/PDLIM1 kinases. Bioinformatic analysis suggests that residues Gly-193 to Leu-507 comprise the catalytic domain, residues Gly-193 to Lys-219 form the ATPbinding cassette (with Tyr-166 as an autophosphorylated regulatory residue), and residues Asp-384 to Glu-417 form an activation loop (Fig. 1). PINK1 is transcriptionally transactivated by the PTEN gene (9) and is expressed at variable levels in different cancer cell types. Valente et al. showed that overexpressed, epitope-tagged PINK1 localized to mitochondria and may have a protective function against cell death (1).To further investigate the role of PINK1 in neuronal ap...

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Section: Discussionmentioning

confidence: 92%

Wild-type PINK1 Prevents Basal and Induced Neuronal Apoptosis, a Protective Effect Abrogated by Parkinson Disease-related Mutations

Petit

Kawarai²,

Paitel³

et al. 2005

Journal of Biological Chemistry

297

243

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“…Because Ru360 abolished this effect, we can conclude that the downstream effects of mitochondria-associated ␣Syn were dependent on the uptake of Ca 2ϩ into the mitochondrial matrix. Previous reports suggest that overexpressing ␣Syn in cells or animals leads to alterations in mitochondrial morphology or function in the absence of overt Ca 2ϩ stress (27,31,36,37,58,59,70,71). These results could be explained by one or more of the following possibilities.…”

Section: Discussionmentioning

confidence: 99%

Soluble, Prefibrillar α-Synuclein Oligomers Promote Complex I-dependent, Ca2+-induced Mitochondrial Dysfunction

Luth

Stavrovskaya

Bartels

et al. 2014

Journal of Biological Chemistry

250

181

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“…Similar to other PD genes, α-synuclein has been shown to variably influence cellular responses to a number of oxidative and metabolic stresses [16][17][18][19]. The mechanisms responsible for these effects have not been firmly established.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial translocation of α-synuclein is promoted by intracellular acidification

Cole

DiEuliis

Leo

et al. 2008

Experimental Cell Research

179

164

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Mitochondrial dysfunction plays a central role in the selective vulnerability of dopaminergic neurons in Parkinson's disease (PD) and is influenced by both environmental and genetic factors. Expression of the PD protein α-synuclein or its familial mutants often sensitizes neurons to oxidative stress and to damage by mitochondrial toxins. This effect is thought to be indirect, since little evidence physically linking α-synuclein to mitochondria has been reported. Here, we show that the distribution of α-synuclein within neuronal and non-neuronal cells is dependent on intracellular pH. Cytosolic acidification induces translocation of α-synuclein from the cytosol onto the surface of mitochondria. Translocation occurs rapidly under artificially-induced low pH conditions and as a result of pH changes during oxidative or metabolic stress. Binding is likely facilitated by low pH-induced exposure of the mitochondria-specific lipid cardiolipin. These results imply a direct role for α-synuclein in mitochondrial physiology, especially under pathological conditions, and in principle, link α-synuclein to other PD genes in regulating mitochondrial homeostasis.

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Effect of the overexpression of wild‐type or mutant α‐synuclein on cell susceptibility to insult

Cited by 226 publications

References 53 publications

Wild-type PINK1 Prevents Basal and Induced Neuronal Apoptosis, a Protective Effect Abrogated by Parkinson Disease-related Mutations

Wild-type PINK1 Prevents Basal and Induced Neuronal Apoptosis, a Protective Effect Abrogated by Parkinson Disease-related Mutations

Soluble, Prefibrillar α-Synuclein Oligomers Promote Complex I-dependent, Ca2+-induced Mitochondrial Dysfunction

Mitochondrial translocation of α-synuclein is promoted by intracellular acidification

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