The deubiquitinase USP9X binds and deubiquitinates alpha-synuclein (SNCA) in vitro and in vivo, showing co-accumulation with SNCA in Lewy Bodies. Knockdown of USP9X expression in conditions of proteolytic inhibition leads to the accumulation of monoubiquitinated SNCA and increases the aggregation of SNCA into toxic inclusions, strengthening the connection between monoubiquitination, inclusion formation, and toxicity of SNCA. USP9X cytosolic levels are lower in Diffuse Lewy Body disease and Parkinson's Disease tissues, which may contribute to the accumulation and aggregation of monoubiquitinated SNCA (Rott et al. 2011).
cysteine-type peptidase activity of USP9X:Ub-SNCA [cytosol]