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.
Highlights
The protein alpha-synuclein plays a major role in Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy
Previous studies have shown that alpha-synuclein can be ubiquitinated by Nedd4, a member of the HECT-WW family of ubiquitin ligases, and that Nedd4 may serve to limit the concentration of alpha-synuclein and the extent of cellular toxicity [4]
We have recently shown that activation of Nedd4 ligases by PY-containing sequences is greatly enhanced if the PY motifs are clustered in large arrays, with the presence of these arrays helping to keep the ligase in an active conformation [20]
Summary
The protein alpha-synuclein plays a major role in Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy. In these diseases, brain cells accumulate aggregates of altered alpha-synuclein that has formed beta-sheet filaments, and this transformation into beta-sheet polymers is thought to underlie cellular toxicity and disease [1]. Previous studies have shown that alpha-synuclein can be ubiquitinated by Nedd, a member of the HECT-WW family of ubiquitin ligases, and that Nedd may serve to limit the concentration of alpha-synuclein and the extent of cellular toxicity [4]. Overexpression of Nedd can increase endosomal degradation of alpha-synuclein and protect cell viability [5, 6]. Alpha-synuclein does not contain a canonical PY sequence, but has proline-rich stretches near its C terminus, and it has been suggested
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