Ubiquitination of alpha-synuclein filaments by Nedd4 ligases

• Published in: PloS one Vol. 13; no. 7; p. e0200763
• Main Authors: Mund, Thomas, Masuda-Suzukake, Masami, Goedert, Michel, Pelham, Hugh R
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 18-07-2018; Public Library of Science (PLoS)
• Subjects: alpha-Synuclein - metabolism; Atrophy; Biology and Life Sciences; Cellular proteins; Clustering; Degradation; Dementia disorders; Disease; Filaments; HEK293 Cells; HeLa Cells; Humans; Laboratories; Lewy bodies; Ligases; Medicine and Health Sciences; Molecular biology; Monomers; Nedd4 Ubiquitin Protein Ligases - metabolism; Parkinson's disease; Parkinsons disease; Physical Sciences; Physiological aspects; Properties; Protein Binding; Protein structure; Proteins; Recognition; Research and Analysis Methods; Substrates; Synuclein; Toxicity; Ubiquitin; Ubiquitin-proteasome system; Ubiquitin-protein ligase; Ubiquitination; Ubiquitination - genetics; Ubiquitination - physiology; United Kingdom > UK
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0200763

Alpha-synuclein can form beta-sheet filaments, the accumulation of which plays a key role in the development of Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. It has previously been shown that alpha-synuclein is a substrate for the HECT domain-containing ubiquitin ligase Nedd4, and is subject to ubiquitin-mediated endosomal degradation. We show here that alpha-synuclein filaments are much better substrates for ubiquitination in vitro than monomeric alpha-synuclein, and that this increased susceptibility cannot be mimicked by the mere clustering of monomers. Recognition by Nedd4 family enzymes is not through the conventional binding of PPxY-containing sequences to WW domains of the ligase, but it also involves C2 and HECT domains. The disease-causing alpha-synuclein mutant A53T is a much less efficient substrate for Nedd4 ligases than the wild-type protein. We suggest that preferential recognition, ubiquitination and degradation of beta-sheet-containing filaments may help to limit toxicity, and that A53T alpha-synuclein may be more toxic, at least in part because it avoids this fate.