α-Synuclein is an abundant brain protein that binds to lipid membranes and is involved in the recycling of presynaptic vesicles. In Parkinson disease, α-synuclein accumulates in intraneuronal inclusions often containing ubiquitin chains. Here we show that the ubiquitin ligase Nedd4, which functions in the endosomal-lysosomal pathway, robustly ubiquitinates α-synuclein, unlike ligases previously implicated in its degradation. Purified Nedd4 recognizes the carboxyl terminus of α-synuclein (residues 120-133) and attaches K63-linked ubiquitin chains. In human cells, Nedd4 overexpression enhances α-synuclein ubiquitination and clearance by a lysosomal process requiring components of the endosomal-sorting complex required for transport. Conversely, Nedd4 down-regulation increases α-synuclein content. In yeast, disruption of the Nedd4 ortholog Rsp5p decreases α-synuclein degradation and enhances inclusion formation and α-synuclein toxicity. In human brains, Nedd4 is present in pigmented neurons and is expressed especially strongly in neurons containing Lewy bodies. Thus, ubiquitination by Nedd4 targets α-synuclein to the endosomal-lysosomal pathway and, by reducing α-synuclein content, may help protect against the pathogenesis of Parkinson disease and other α-synucleinopathies.
Proc Natl Acad Sci U S A
17004 - 17009
Amino Acid Sequence, Animals, Binding Sites, Brain, Cell Line, Endosomal Sorting Complexes Required for Transport, Endosomes, HEK293 Cells, Humans, In Vitro Techniques, Lewy Bodies, Locus Coeruleus, Lysine, Lysosomes, Mice, Molecular Sequence Data, Nedd4 Ubiquitin Protein Ligases, Parkinson Disease, Rats, Recombinant Proteins, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Substantia Nigra, Substrate Specificity, Ubiquitin-Protein Ligase Complexes, Ubiquitin-Protein Ligases, Ubiquitination, alpha-Synuclein