Ubiquitination of alpha-synuclein filaments by Nedd4 ligases.

Abstract

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.

• Authors: Thomas Mund, Masami Masuda-Suzukake, Michel Goedert, Hugh R Pelham
• Journal: PloS one (PLoS One) Vol. 13 Issue 7 Pg. e0200763 ( 2018) ISSN: 1932-6203 [Electronic] United States
• PMID: 30021006 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• alpha-Synuclein
• Nedd4 Ubiquitin Protein Ligases
• Nedd4 protein, human

Topics

• HEK293 Cells
• HeLa Cells
• Humans
• Nedd4 Ubiquitin Protein Ligases (metabolism)
• Protein Binding
• Ubiquitination (genetics, physiology)
• alpha-Synuclein (metabolism)