Ubiquitination of alpha-synuclein filaments by Nedd4 ligases.

PloS One
Thomas MundHugh R Pelham

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.

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Citations

May 10, 2019·Journal of Neurochemistry·Leonidas StefanisGeorge K Tofaris
Apr 8, 2020·Frontiers in Aging Neuroscience·Sarah M HernandezAndrey L Karamyshev
Aug 1, 2019·Cellular and Molecular Life Sciences : CMLS·Hiroshi Ageta, Kunihiro Tsuchida
Jul 25, 2020·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·TaeHee KimRaghu Vemuganti
Jul 28, 2020·The Neuroscientist : a Review Journal Bringing Neurobiology, Neurology and Psychiatry·Shubhangini Tiwari, Sarika Singh
Nov 20, 2020·Cell Death and Differentiation·François Le Guerroué, Richard J Youle
Apr 26, 2020·Protein Expression and Purification·A Katherine Hatstat, Dewey G McCafferty
Oct 16, 2021·ACS Chemical Neuroscience·A Katherine HatstatDewey G McCafferty

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Methods Mentioned

BETA
ubiquitination
autoubiquitination
pull downs
transfections
transfection

Software Mentioned

Trabid

Related Concepts

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