Impaired degradation of mutant α-synuclein by chaperone-mediated autophagy

Ana Maria Cuervo, Leonidas Stafanis, Ross Fredenburg, Peter T. Lansbury, David Sulzer

Research output: Contribution to journalArticle

1233 Scopus citations

Abstract

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

Original languageEnglish (US)
Pages (from-to)1292-1295
Number of pages4
JournalScience
Volume305
Issue number5688
DOIs
StatePublished - Aug 27 2004

    Fingerprint

ASJC Scopus subject areas

  • General

Cite this

Cuervo, A. M., Stafanis, L., Fredenburg, R., Lansbury, P. T., & Sulzer, D. (2004). Impaired degradation of mutant α-synuclein by chaperone-mediated autophagy. Science, 305(5688), 1292-1295. https://doi.org/10.1126/science.1101738