Ubiquitination of alpha-synuclein filaments by Nedd4 ligases.

Autor: Mund T; MRC Laboratory of Molecular Biology, Cambridge, United Kingdom., Masuda-Suzukake M; MRC Laboratory of Molecular Biology, Cambridge, United Kingdom., Goedert M; MRC Laboratory of Molecular Biology, Cambridge, United Kingdom., Pelham HR; MRC Laboratory of Molecular Biology, Cambridge, United Kingdom.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2018 Jul 18; Vol. 13 (7), pp. e0200763. Date of Electronic Publication: 2018 Jul 18 (Print Publication: 2018).
DOI: 10.1371/journal.pone.0200763
Abstrakt: 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.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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