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.
Mesh Terms:
Amino Acid Motifs, Animals, Antigens, CD, Autophagy, Cells, Cultured, Glyceraldehyde-3-Phosphate Dehydrogenases, Half-Life, Intracellular Membranes, Lysosome-Associated Membrane Glycoproteins, Lysosomes, Male, Mice, Molecular Chaperones, Mutation, Nerve Tissue Proteins, Neurons, PC12 Cells, Protein Binding, Protein Transport, Rats, Rats, Wistar, Synucleins, alpha-Synuclein
Amino Acid Motifs, Animals, Antigens, CD, Autophagy, Cells, Cultured, Glyceraldehyde-3-Phosphate Dehydrogenases, Half-Life, Intracellular Membranes, Lysosome-Associated Membrane Glycoproteins, Lysosomes, Male, Mice, Molecular Chaperones, Mutation, Nerve Tissue Proteins, Neurons, PC12 Cells, Protein Binding, Protein Transport, Rats, Rats, Wistar, Synucleins, alpha-Synuclein
Science
Date: Aug. 27, 2004
PubMed ID: 15333840
View in: Pubmed Google Scholar
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