title: Enhanced ubiquitin-dependent degradation by Nedd4 protects against α-synuclein accumulation and toxicity in animal models of Parkinson's disease.
abstract: Parkinson's disease is a neurodegenerative disorder, characterized by accumulation and misfolding of α-synuclein. Although the level of α-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 α-synuclein accumulation in vivo. The ubiquitin ligase Nedd4 targets α-synuclein to the endosomal-lysosomal pathway in cultured cells. Here we asked whether Nedd4-mediated degradation protects against α-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 α-synuclein in the Drosophila eye. Overexpressed Nedd4 in the Drosophila brain prevented the α-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 wild-type but not the catalytically inactive Nedd4 decreased the α-synuclein-induced dopaminergic cell loss in the rat substantia nigra and reduced α-synuclein accumulation. Collectively, our data in two evolutionarily distant model organisms strongly suggest that Nedd4 is a modifier of α-synuclein pathobiology and thus a potential target for neuroprotective therapies.
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, UK; Oxford Parkinson's Disease Centre, University of Oxford, UK; MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, UK.
authors.forename: Sian E
authors.initials: SE
authors.lastname: Davies
authors.affiliation: Neuroregeneration Research Institute, McLean Hospital, Harvard Medical School, USA.
authors.forename: Penelope J
authors.initials: PJ
authors.lastname: Hallett
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, UK; Oxford Parkinson's Disease Centre, University of Oxford, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Moens
authors.affiliation: Neuroregeneration Research Institute, McLean Hospital, Harvard Medical School, USA.
authors.forename: Gaynor
authors.initials: G
authors.lastname: Smith
authors.affiliation: Neuroregeneration Research Institute, McLean Hospital, Harvard Medical School, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Mangano
authors.affiliation: Department of Cell Biology, Harvard Medical School, USA.
authors.forename: Hyoung Tae
authors.initials: HT
authors.lastname: Kim
authors.affiliation: Department of Cell Biology, Harvard Medical School, USA.
authors.forename: Alfred L
authors.initials: AL
authors.lastname: Goldberg
authors.affiliation: MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, UK.
authors.forename: Ji-Long
authors.initials: JL
authors.lastname: Liu
authors.affiliation: Neuroregeneration Research Institute, McLean Hospital, Harvard Medical School, USA.
authors.forename: Ole
authors.initials: O
authors.lastname: Isacson
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, UK; Oxford Parkinson's Disease Centre, University of Oxford, UK. Electronic address: george.tofaris@ndcn.ox.ac.uk.
authors.forename: George K
authors.initials: GK
authors.lastname: Tofaris
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001921:Brain / Q000378:metabolism / Q000473:pathology; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology; D004330:Drosophila; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism*; D005123:Eye / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008124:Locomotion / Q000502:physiology; D008297:Male; D009154:Mutation; D000075702:Nedd4 Ubiquitin Protein Ligases; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D020734:Parkinsonian Disorders / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D012333:RNA, Messenger; D051844:alpha-Synuclein; C000618479:NEDD4L protein, rat; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; C000618484:Nedd4 protein, rat; D044767:Ubiquitin-Protein Ligases
keywords: Endosomal-trafficking; Lysosome; Protein-degradation; Ubiquitination