Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy.
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.
Cuervo
Ana Maria
AM
Department of Anatomy and Structural Biology, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA. amcuervo@aecom.yu.edu
Stefanis
Leonidas
L
Fredenburg
Ross
R
Lansbury
Peter T
PT
Sulzer
David
D
D020816:Amino Acid Motifs; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001343:Autophagy; D002478:Cells, Cultured; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism / Q000494:pharmacology; D006207:Half-Life; D007425:Intracellular Membranes / Q000378:metabolism; D051907:Lysosomal Membrane Proteins; D008247:Lysosomes / Q000378:metabolism*; D008297:Male; D051379:Mice; D018832:Molecular Chaperones / Q000378:metabolism*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D016716:PC12 Cells; D011485:Protein Binding; D021381:Protein Transport; D051381:Rats; D017208:Rats, Wistar; D051843:Synucleins; D051844:alpha-Synuclein
D015703:Antigens, CD; D051907:Lysosomal Membrane Proteins; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; C497605:Snca protein, mouse; C497606:Snca protein, rat; D051843:Synucleins; D051844:alpha-Synuclein; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases