Impaired Degradation of Mutant α-Synuclein by Chaperone-Mediated Autophagy
Brigham and Women's Hospital · Albert Einstein College of Medicine · +3 more institutions
Abstract
Aberrant alpha-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 alpha-synuclein is normally degraded. We found that wild-type alpha-synuclein was selectively translocated into lysosomes for degradation by the chaperone-mediated autophagy pathway. The pathogenic A53T and A30P alpha-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…
Citation impact
- FWCI
- 34.25
- Percentile
- 100%
- References
- 29
Authors
5- AMAna María CuervoCorresponding
Brigham and Women's Hospital, Albert Einstein College of Medicine, Academy of Athens, New York Psychoanalytic Society and Institute, Biomedical Research Foundation of the Academy of Athens
- LSLeonidas Stefanis
Brigham and Women's Hospital, Albert Einstein College of Medicine, Academy of Athens, New York Psychoanalytic Society and Institute, Biomedical Research Foundation of the Academy of Athens
- RARoss A. Fredenburg
Brigham and Women's Hospital, Albert Einstein College of Medicine, Academy of Athens, New York Psychoanalytic Society and Institute, Biomedical Research Foundation of the Academy of Athens
- PTPeter T. Lansbury
Brigham and Women's Hospital, Albert Einstein College of Medicine, Academy of Athens, New York Psychoanalytic Society and Institute, Biomedical Research Foundation of the Academy of Athens
- DSDavid Sulzer
Brigham and Women's Hospital, Albert Einstein College of Medicine, Academy of Athens, New York Psychoanalytic Society and Institute, Biomedical Research Foundation of the Academy of Athens
Topics & keywords
- Autophagy
- Alpha-synuclein
- Mutant
- Cell biology
- Chaperone (clinical)
- Inclusion bodies
- Pathogenesis
- Biology