Pathogenetic mechanisms of parkin in Parkinson's disease.

摘要

CONTEXT: The cause and pathogenesis of Parkinson's disease remain unknown; mitochondrial dysfunction, oxidative damage, environmental factors, and genetic predisposition might all be involved. Identification of the causative genes for familial Parkinson's diseases allow study of the pathogenesis of the disease at the molecular level. STARTING POINT: Katja Hedrich and colleagues studied 75 Serbian patients with early-onset Parkinson's disease for DJ-1 mutations (Neurology 2004; 62: 389-94). One patient was a compound heterozygote and another had a heterozygous exon deletion. DJ-1 mutations seem to be rare in this European population. By contrast, parkin mutations have been found in about 50% of familial cases and in 10-20% of cases without a positive family history. WHERE NEXT: The fact that parkin is a ubiquitin ligase gives special meaning to the molecular mechanism of neurodegeneration in general. In Parkinson's disease, Lewy bodies are immunoreactive for ubiquitin. Accumulation of abnormal proteins has also been seen in other neurodegenerative disorders. Disturbance of protein degradation by the ubiquitin-proteasome system might have a critical role in neurodegeneration. Although alpha-synuclein mutations are infrequent, alpha-synuclein accumulates in Lewy bodies, and alpha-synuclein fibrils impair the 26S proteasome function. UCH-L1 is also an abundant deubiquitylating enzyme, and its mutation is linked to PARK5. Furthermore, DJ-1 might interact with SUMO-1 (small ubiquitin-like modifier), which can counteract ubiquitin and stabilise proteins against degradation by the 26S proteasome. Uncovering the mechanisms of protein degradation should add importantly to understanding the neurodegenerative process in these neurodegenerative diseases.