Deubiquitinase Usp8 regulates α-synuclein clearance and modifies its toxicity in Lewy body disease
- 21 July 2016
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 113 (32), 201523597-E4697
- https://doi.org/10.1073/pnas.1523597113
Abstract
In Parkinson’s disease, misfolded α-synuclein accumulates, often in a ubiquitinated form, in neuronal inclusions termed Lewy bodies. An important outstanding question is whether ubiquitination in Lewy bodies is directly relevant to α-synuclein trafficking or turnover and Parkinson’s pathogenesis. By comparative analysis in human postmortem brains, we found that ubiquitin immunoreactivity in Lewy bodies is largely due to K63-linked ubiquitin chains and markedly reduced in the substantia nigra compared with the neocortex. The ubiquitin staining in cells with Lewy bodies inversely correlated with the content and pathological localization of the deubiquitinase Usp8. Usp8 interacted and partly colocalized with α-synuclein in endosomal membranes and, both in cells and after purification, it deubiquitinated K63-linked chains on α-synuclein. Knockdown of Usp8 in the Drosophila eye reduced α-synuclein levels and α-synuclein–induced eye toxicity. Accordingly, in human cells, Usp8 knockdown increased the lysosomal degradation of α-synuclein. In the dopaminergic neurons of the Drosophila model, unlike knockdown of other deubiquitinases, Usp8 protected from α-synuclein–induced locomotor deficits and cell loss. These findings strongly suggest that removal of K63-linked ubiquitin chains on α-synuclein by Usp8 is a critical mechanism that reduces its lysosomal degradation in dopaminergic neurons and may contribute to α-synuclein accumulation in Lewy body disease.Funding Information
- Wellcome Trust (97479/Z/11/X)
- Oxford Biomedical Research Centre (N/A)
This publication has 45 references indexed in Scilit:
- Recurrent gain-of-function USP8 mutations in Cushing's diseaseCell Research, 2015
- Synaptic Strength Is Bidirectionally Controlled by Opposing Activity-Dependent Regulation of Nedd4-1 and USP8Journal of Neuroscience, 2014
- Lys-63-linked Ubiquitination by E3 Ubiquitin Ligase Nedd4-1 Facilitates Endosomal Sequestration of Internalized α-SynucleinOnline Journal of Public Health Informatics, 2014
- Physiological Characterisation of Human iPS-Derived Dopaminergic NeuronsPLOS ONE, 2014
- Why do cellular proteins linked to K63-polyubiquitin chains not associate with proteasomes?The EMBO Journal, 2013
- Cognitive impairment, decline and fluctuations in older community-dwelling subjects with Lewy bodiesBrain, 2012
- Tyrosine and serine phosphorylation of α-synuclein have opposing effects on neurotoxicity and soluble oligomer formationJCI Insight, 2009
- Phosphorylation of Ser-129 Is the Dominant Pathological Modification of α-Synuclein in Familial and Sporadic Lewy Body DiseaseJournal of Biological Chemistry, 2006
- Phosphorylated α-Synuclein Is Ubiquitinated in α-Synucleinopathy LesionsOnline Journal of Public Health Informatics, 2002
- Deubiquitination Step in the Endocytic Pathway of Yeast Plasma Membrane Proteins: Crucial Role of Doa4p Ubiquitin IsopeptidaseMolecular and Cellular Biology, 2001