AlphasynucleinandParkinmediatedproteolysisinParkinsonsdisease

The motor defects of Parkinson's disease are related to the loss of dopaminergic neurons in specific brain regions. Examination of these neurons in diseased tissue has revealed the presence of Lewy bodies, dense aggregates that include the protein alpha-synuclein. A genetic basis for most cases of Parkinson's disease has not yet been identified, but mutations in alpha-synuclein have been associated with at least one rare form of the disease, and mutations in another protein, the parkin gene, are associated with another inherited form of Parkinson's disease. Parkin is found in Lewy bodies along with alpha-synuclein and the parkin protein is an enzyme, an E3 ubiquitin ligase. This ligase tags specific proteins in normal cells with ubiquitin, targeting them for destruction in the proteosome (see Proteosome pathway). One of the proteins that parkin normally targets for destruction is a specific O-glycosylated form of alpha-synuclein. Failure of parkin-mediated degradation of alpha-synuclein may be a key factor leading to the death of dopaminergic neurons. Another substrate of parkin is a GPCR-like protein called Pael-R that accumulates in the ER of affected cells and may cause neuronal cell death. The involvement of Parkin and alpha-synuclein mutations in genetic forms of Parkinson's suggest that failure of ubiquitination and protein degradation may be causative in other forms of Parkinson's. Questions remaining include the cause of the lack of effective ubiquitination in individuals lacking obvious genetic defects in this pathway and how to use this knowledge of ubiquitination and protein degradation in Parkinson's disease to identify therapeutic strategies.

Contributor: Glenn Croston, PhD

REFERENCES: Jellinger KA. Morphological substrates of mental dysfunction in Lewy body disease: an update. J Neural Transm Suppl 2000;59:185-212 Tanaka Y., et al. Inducible expression of mutant alpha-synuclein decrease proteasome activity and increases sensitivity to mitochondria-dependent apoptosis. Hum Mol Genet 2001 Apr 15; 10(9):919-26