Impaired Degradation of Mutant α-Synuclein by Chaperone-Mediated Autophagy

• DOI: 10.1126/science.1101738
• Publication Date: 2004-08-26T21:14:15Z
• Authors: Ana Maria Cuervo; Leonidas Stefanis; Ross Fredenburg; Peter T. Lansbury; David Sulzer
• Keywords: Chaperone (clinical); Inclusion bodies; Pathogenesis; Wild type; Lewy body

Aberrant alpha-synuclein degradation is implicated in Parkinson's disease pathogenesis because the protein accumulates Lewy inclusion bodies associated with disease. Little known, however, about pathways by which wild-type normally degraded. We found that was selectively translocated into lysosomes for chaperone-mediated autophagy pathway. The pathogenic A53T and A30P mutants bound to receptor this pathway on lysosomal membrane, but appeared act as uptake blockers, inhibiting both their own of other substrates. These findings may underlie toxic gain-of-function mutants.