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Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease.

Nature medicine | Oct 8, 2001

http://www.ncbi.nlm.nih.gov/pubmed/11590439

Parkinson disease is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons and the presence of intracytoplasmic-ubiquitinated inclusions (Lewy bodies). Mutations in alpha-synuclein (A53T, A30P) and parkin cause familial Parkinson disease. Both these proteins are found in Lewy bodies. The absence of Lewy bodies in patients with parkin mutations suggests that parkin might be required for the formation of Lewy bodies. Here we show that parkin interacts with and ubiquitinates the alpha-synuclein-interacting protein, synphilin-1. Co-expression of alpha-synuclein, synphilin-1 and parkin result in the formation of Lewy-body-like ubiquitin-positive cytosolic inclusions. We further show that familial-linked mutations in parkin disrupt the ubiquitination of synphilin-1 and the formation of the ubiquitin-positive inclusions. These results provide a molecular basis for the ubiquitination of Lewy-body-associated proteins and link parkin and alpha-synuclein in a common pathogenic mechanism through their interaction with synphilin-1.

Pubmed ID: 11590439 RIS Download

Mesh terms: Animals | Carrier Proteins | Cell Line | Glycosylation | Humans | Lewy Bodies | Ligases | Mutagenesis | Nerve Tissue Proteins | Parkinson Disease | Rats | Synucleins | Ubiquitin-Protein Ligases | Ubiquitins | alpha-Synuclein

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Associated grants

  • Agency: NINDS NIH HHS, Id: NS38377

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