α-Synuclein fate is determined by USP9X-regulated monoubiquitination
Open Access
- 7 November 2011
- 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. 108 (46), 18666-18671
- https://doi.org/10.1073/pnas.1105725108
Abstract
α-Synuclein is central to the pathogenesis of Parkinson disease (PD). Mutations as well as accumulation of α-synuclein promote the death of dopaminergic neurons and the formation of Lewy bodies. α-Synuclein is monoubiquitinated by SIAH, but the regulation and roles of monoubiquitination in α-synuclein biology are poorly understood. We now report that the deubiquitinase USP9X interacts in vivo with and deubiquitinates α-synuclein. USP9X levels are significantly lower in cytosolic fractions of PD substantia nigra and Diffuse Lewy Body disease (DLBD) cortices compared to controls. This was associated to lower deubiquitinase activity toward monoubiquitinated α-synuclein in DLBD cortical extracts. A fraction of USP9X seems to be aggregated in PD and DLBD, as USP9X immunoreactivity is detected in Lewy bodies. Knockdown of USP9X expression promotes accumulation of monoubiquitinated α-synuclein species and enhances the formation of toxic α-synuclein inclusions upon proteolytic inhibition. On the other hand, by manipulating USP9X expression levels in the absence of proteolytic impairment, we demonstrate that monoubiquitination controls the partition of α-synuclein between different protein degradation systems. Deubiquitinated α-synuclein is mostly degraded by autophagy, while monoubiquitinated α-synuclein is preferentially degraded by the proteasome. Moreover, monoubiquitination promotes the degradation of α-synuclein, whereas deubiquitination leads to its accumulation, suggesting that the degradation of deubiquitinated α-synuclein by the autophagy pathway is less efficient than the proteasomal one. Lower levels of cytosolic USP9X and deubiquitinase activity in α-synucleinopathies may contribute to the accumulation and aggregation of monoubiquitinated α-synuclein in Lewy bodies. Our data indicate that monoubiquitination is a key determinant of α-synuclein fate.Keywords
This publication has 30 references indexed in Scilit:
- Ubiquitinylation of α-Synuclein by Carboxyl Terminus Hsp70-Interacting Protein (CHIP) Is Regulated by Bcl-2-Associated Athanogene 5 (BAG5)PLOS ONE, 2011
- Genetic Animal Models of Parkinson's DiseaseNeuron, 2010
- Dependence of Phospholipase D1 Multi-monoubiquitination on Its Enzymatic Activity and PalmitoylationJournal of Biological Chemistry, 2010
- Region-Specific Protein Abundance Changes in the Brain of MPTP-Induced Parkinson’s Disease Mouse ModelJournal of Proteome Research, 2010
- Inclusion formation and neuronal cell death through neuron-to-neuron transmission of α-synucleinProceedings of the National Academy of Sciences, 2009
- Synphilin-1A Inhibits Seven in Absentia Homolog (SIAH) and Modulates α-Synuclein Monoubiquitylation and Inclusion FormationJournal of Biological Chemistry, 2009
- Monoubiquitylation of α-Synuclein by Seven in Absentia Homolog (SIAH) Promotes Its Aggregation in Dopaminergic CellsJournal of Biological Chemistry, 2008
- Ubiquitination of -synuclein by Siah-1 promotes -synuclein aggregation and apoptotic cell deathHuman Molecular Genetics, 2007
- Phosphorylated α-Synuclein Is Ubiquitinated in α-Synucleinopathy LesionsJournal of Biological Chemistry, 2002
- Ubiquitination of a New Form of α-Synuclein by Parkin from Human Brain: Implications for Parkinson's DiseaseScience, 2001