Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase

Autosomal recessive juvenile parkinsonism (AR-JP). one of the most common f amilial forms of Parkinson disease, is characterized by selective dopaminer gic neural cell death and the absence of the Lewy body, a cytoplasmic inclu sion body consisting of aggregates of abnormally accumulated proteins(1). W e previously cloned PARK2, mutations of which cause AR-JP (ref. 2). but the function of the gene product, parkin. remains unknown. We report here that parkin is involved in protein degradation as a ubiquitin-protein ligase co llaborating with the ubiquitin-conjugating enzyme UbcH7. and that mutant pa rkins from AR-JP patients show loss of the ubiquitin-protein ligase activit y. Our findings indicate that accumulation of proteins that have yet to be identified causes a selective neural cell death without formation of Lewy b odies. Our findings should enhance the exploration of the molecular mechani sms of neurodegeneration in Parkinson disease as well as in other neurodege nerative diseases that are characterized by involvement of abnormal protein ubiquitination. including Alzheimer disease, other tauopathies. CAG triple t repeat disorders and amyotrophic lateral sclerosis(3-10).