Enhanced ubiquitin-dependent degradation by Nedd4 protects against α-synuclein accumulation and toxicity in animal models of Parkinson's disease

Parkinson's disease is a neurodegenerative disorder, characterized by accumulation and misfolding of alpha-synuclein. Although the level of ot-synuclein in neurons is fundamentally linked to the onset of neurodegeneration, multiple pathways have been implicated in its degradation, and it remains unclear which are the critical ubiquitination enzymes that protect against alpha-synudein accumulation in vivo. The ubiquitin ligase Nedd4 targets a-synuclein to the endosomal-lysosomal pathway in cultured cells. Here we asked whether Nedd4 mediated degradation protects against a-synuclein-induced toxicity in the Drosophila and rodent models of Parkinson's disease. We show that overexpression of Nedd4 can rescue the degenerative phenotype from ectopic expression of ot-synuclein in the Drosophila eye. Overexpressed Nedd4 in the Drosophila brain prevented the alpha-synuclein-induced locomotor defect whereas reduction in endogenous Nedd4 by RNAi led to worsening motor function and increased loss of dopaminergic neurons. Accordingly, AAV-mediated expression of wildtype but not the catalytically inactive Nedd4 decreased the a-synuclein-induced dopaminergic cell loss in the rat substantia nigra and reduced a-synuclein accumulation. Collectively, our data in two evolutionarily distant model organisms strongly suggest that Nedd4 is a modifier of alpha-synuclein pathobiology and thus a potential target for neuroprotective therapies. (c) 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).