title: Ubiquitin ligase Nedd4 promotes alpha-synuclein degradation by the endosomal-lysosomal pathway.
abstract: 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.
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: George K
authors.initials: GK
authors.lastname: Tofaris
authors.forename: Hyoung Tae
authors.initials: HT
authors.lastname: Kim
authors.forename: Raphael
authors.initials: R
authors.lastname: Hourez
authors.forename: Jin-Woo
authors.initials: JW
authors.lastname: Jung
authors.forename: Kwang Pyo
authors.initials: KP
authors.lastname: Kim
authors.forename: Alfred L
authors.initials: AL
authors.lastname: Goldberg
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D016631:Lewy Bodies / Q000378:metabolism; D008125:Locus Coeruleus / Q000378:metabolism; D008239:Lysine / Q000737:chemistry; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D000075702:Nedd4 Ubiquitin Protein Ligases; D010300:Parkinson Disease / Q000209:etiology / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism; D013379:Substrate Specificity; D043743:Ubiquitin-Protein Ligase Complexes / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D011994:Recombinant Proteins; D029701:Saccharomyces cerevisiae Proteins; D051844:alpha-Synuclein; D043743:Ubiquitin-Protein Ligase Complexes; C000618479:NEDD4L protein, rat; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; C000618484:Nedd4 protein, rat; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases; C469287:RSP5 protein, S cerevisiae; D008239:Lysine