Deubiquitinase Usp8 regulates α-synuclein clearance and modifies its toxicity in Lewy body disease
Alexopoulou Z., Lang J., Perrett RM., Elschami M., Hurry MED., Kim HT., Mazaraki D., Szabo A., Kessler BM., Goldberg AL., Ansorge O., Fulga TA., Tofaris GK.
Significance A cardinal feature of Parkinson’s disease pathology is the aggregation of α-synuclein in ubiquitin-positive inclusions termed Lewy bodies, yet the composition of ubiquitin conjugates in these inclusions and their role in α-synuclein pathobiology remain unclear. Here we demonstrate that α-synuclein inclusions contain K63-linked ubiquitin chains, which are strikingly reduced in dopaminergic neurons. In these neurons, the deubiquitinase Usp8 is present in Lewy bodies, and its content is related inversely to the extent of K63-linked ubiquitination. Our mechanistic studies in vitro and in flies indicate that Usp8 interacts with and deconjugates K63-linked ubiquitin chains on α-synuclein, prolonging its half-life and increasing its toxicity. Thus, Usp8 appears to be a critical factor determining α-synuclein levels that could be targeted for therapies.