Ubiquitin ligase Nedd4 promotes alpha-synuclein degradation by the endosomal-lysosomal pathway.

ABSTRACT: ?-Synuclein is an abundant brain protein that binds to lipid membranes and is involved in the recycling of presynaptic vesicles. In Parkinson disease, ?-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 ?-synuclein, unlike ligases previously implicated in its degradation. Purified Nedd4 recognizes the carboxyl terminus of ?-synuclein (residues 120-133) and attaches K63-linked ubiquitin chains. In human cells, Nedd4 overexpression enhances ?-synuclein ubiquitination and clearance by a lysosomal process requiring components of the endosomal-sorting complex required for transport. Conversely, Nedd4 down-regulation increases ?-synuclein content. In yeast, disruption of the Nedd4 ortholog Rsp5p decreases ?-synuclein degradation and enhances inclusion formation and ?-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 ?-synuclein to the endosomal-lysosomal pathway and, by reducing ?-synuclein content, may help protect against the pathogenesis of Parkinson disease and other ?-synucleinopathies.

SUBMITTER: Tofaris GK 

PROVIDER: S-EPMC3193191 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature