Inducible expression of mutant alpha-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependent apoptosis

Tanaka, Yuji

doi:10.1093/hmg/10.9.919

Cited by 464 publications

(291 citation statements)

References 59 publications

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“…Consistent with this hypothesis, neurons exposed to proteasomal inhibitors or proteins prone to aggregation are more vulnerable to cell death (18)(19)(20). To test whether Snitrosylation of XIAP could comprise its ability to protect neurons against proteasomal dysfunction and protein aggregation, we treated cells with proteasomal inhibitor, MG132 (3 M), or expressed an aggregation-prone GFPu protein to induce cell death (21).…”

Section: Xiap S-nitrosylation Impairs Its Ability To Inhibit Caspase-mentioning

confidence: 87%

S-nitrosylation of XIAP compromises neuronal survival in Parkinson's disease

Tsang

Lee

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

147

112

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Inhibitors of apoptosis (IAPs) are a family of highly-conserved proteins that regulate cell survival through binding to caspases, the final executioners of apoptosis. X-linked IAP (XIAP) is the most widely expressed IAP and plays an important function in regulating cell survival. XIAP contains 3 baculoviral IAP repeats (BIRs) followed by a RING finger domain at the C terminal. The BIR domains of XIAP possess anticaspase activities, whereas the RING finger domain enables XIAP to function as an E3 ubiquitin ligase in the ubiquitin and proteasomal system. Our previous study showed that parkin, a protein that is important for the survival of dopaminergic neurons in Parkinson's disease (PD), is S-nitrosylated both in vitro and in vivo in PD patients. S-nitrosylation of parkin compromises its ubiquitin E3 ligase activity and its protective function, which suggests that nitrosative stress is an important factor in regulating neuronal survival during the pathogenesis of PD. In this study we show that XIAP is S-nitrosylated in vitro and in vivo in an animal model of PD and in PD patients. Nitric oxide modifies mainly cysteine residues within the BIR domains. In contrast to parkin, S-nitrosylation of XIAP does not affect its E3 ligase activity, but instead directly compromises its anticaspase-3 and antiapoptotic function. Our results confirm that nitrosative stress contributes to PD pathogenesis through the impairment of prosurvival proteins such as parkin and XIAP through different mechanisms, indicating that abnormal S-nitrosylation plays an important role in the process of neurodegeneration.

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Section: Xiap S-nitrosylation Impairs Its Ability To Inhibit Caspase-mentioning

confidence: 87%

S-nitrosylation of XIAP compromises neuronal survival in Parkinson's disease

Tsang

Lee

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

147

112

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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

180

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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“…We performed hematoxylin and eosin (H & E) staining according to the manufacturer's instructions (Sigma). For immunohistochemistry, cells were fixed with 4% paraformaldehyde for 30 min and permeabilized with 0.2% Triton X-100 for 15 min at room temperature and processed as described previously (Tanaka et al, 2001). Cell preparations were incubated with primary antibodies anti-␣-synuclein, antimyc, anti-phospho-S129 ␣-synuclein, or anti-ubiquitin, then with secondary antibodies Cy3-conjugated anti-mouse or FITC-conjugated antirabbit, nuclei were stained with 4Ј,6-diamidino-2-phenylindole, and all signals were analyzed by fluorescence microscopy (Axiovert 100; Zeiss, Oberkochen, Germany).…”

Section: Methodsmentioning

confidence: 99%

-Synuclein Phosphorylation Enhances Eosinophilic Cytoplasmic Inclusion Formation in SH-SY5Y Cells

Smith

Margolis

et al. 2005

Journal of Neuroscience

247

229

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Parkinson's disease (PD) is a neurodegenerative disorder characterized by selective loss of dopaminergic neurons and the presence of Lewy bodies. Previous reports have shown that ␣-synuclein deposited in brain tissue from individuals with synucleinopathy is extensively phosphorylated at Ser-129. Here, we investigate the role of phosphorylation of ␣-synuclein in the formation of inclusions involving synphilin-1 and parkin using site-directed mutagenesis to change Ser-129 of ␣-synuclein to alanine (S129A) to abolish phosphorylation at this site. Coexpression of wild-type ␣-synuclein and synphilin-1 in human neuroblastoma SH-SY5Y cells yielded cytoplasmic eosinophilic inclusions with some features resembling Lewy bodies, whereas coexpression of S129A ␣-synuclein and synphlin-1 formed few or no inclusions. Moreover, coexpression of parkin with ␣-synuclein and synphilin-1 formed more ubiquitinated inclusions, but these inclusions decreased with expression of S129A ␣-synuclein instead of wild-type ␣-synuclein. Coimmunoprecipitation assays revealed a decreased interaction of S129A ␣-synuclein with synphilin-1 compared with wild-type ␣-synuclein. Expression of S129A ␣-synuclein instead of wild-type ␣-synuclein also decreased the association of synphilin-1 and parkin and subsequently reduced the parkin-mediated ubiquitination of synphilin-1 and the formation of ubiquitinated inclusions. Treatment of SH-SY5Y cells with H 2 O 2 increased ␣-synuclein phosphorylation and enhanced the formation of inclusions formed by coexpression of ␣-synuclein, synphilin-1, and parkin, whereas treatment with the casein kinase 2 inhibitor 5,6-dichloro-1-␤-D-ribofuranosylbenzimidazole had the opposite affect. These results indicate that phosphorylation of ␣-synuclein at S129 may be important for the formation of inclusions in PD and related ␣ synucleinopathies.

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Inducible expression of mutant alpha-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependent apoptosis

Cited by 464 publications

References 59 publications

S-nitrosylation of XIAP compromises neuronal survival in Parkinson's disease

S-nitrosylation of XIAP compromises neuronal survival in Parkinson's disease

Mitochondrial translocation of α-synuclein is promoted by intracellular acidification

-Synuclein Phosphorylation Enhances Eosinophilic Cytoplasmic Inclusion Formation in SH-SY5Y Cells

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