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Science 27 August 2004:
Vol. 305. no. 5688, pp. 1292 - 1295
DOI: 10.1126/science.1101738
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Reports

Impaired Degradation of Mutant {alpha}-Synuclein by Chaperone-Mediated Autophagy

Ana Maria Cuervo,1* Leonidas Stefanis,2 Ross Fredenburg,3 Peter T. Lansbury,3 David Sulzer4

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 mutants.

1 Department of Anatomy and Structural Biology, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
2 Neurobiology Laboratory, Foundation of Biomedical Research of the Academy of Athens, Athens 11527, Greece and Department of Neurology and Pathology, Columbia University, New York, NY 10032, USA.
3 Center for Neurologic Diseases, Brigham and Women's Hospital, Department of Neurology, Harvard MedicalSchool, Cambridge, MA 02139, USA.
4 Departments of Psychiatry and Neurology, Columbia University, Department of Neuroscience, New York State Psychiatric Institute, New York, NY 10032, USA.

* To whom correspondence should be addressed. E-mail: amcuervo{at}aecom.yu.edu

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