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Deubiquitinase Usp8 regulates α-synuclein clearance and modifies its toxicity in Lewy body disease
Abstract
Significance: A cardinal feature of Parkinson’s disease pathology is the aggregation of α-synuclein in ubiquitin-positive inclusions termed Lewy bodies, yet the composition of ubiquitin conjugates in these inclusions and their role in α-synuclein pathobiology remain unclear. Here we demonstrate that α-synuclein inclusions contain K63-linked ubiquitin chains, which are strikingly reduced in dopaminergic neurons. In these neurons, the deubiquitinase Usp8 is present in Lewy bodies, and its content is related inversely to the extent of K63-linked ubiquitination. Our mechanistic studies in vitro and in flies indicate that Usp8 interacts with and deconjugates K63-linked ubiquitin chains on α-synuclein, prolonging its half-life and increasing its toxicity. Thus, Usp8 appears to be a critical factor determining α-synuclein levels that could be targeted for therapies.
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USP8 knockdown leads to increased lysosomal degradation of α-synuclein and protects from α-synuclein-induced toxicity and cell loss in an α-synuclein fly model of PD.
“USP8 knockdown also leads to increased lysosomal degradation of α-synuclein, and it protects from α-synuclein-induced toxicity and cell loss in an α-synuclein fly model of PD [19].”
From USP8 Down-Regulation Promotes Parkin-Independent Mitophagy in the Drosophila Brain and in Human Neurons (2023) · cites this paper as [19]
USP8 down-regulation protects from α-synuclein-induced toxicity in an α-synuclein fly model of PD.
“USP8 down-regulation also protects from α-synuclein-induced toxicity in an α-synuclein fly model of PD [19]”
From USP8 Down-Regulation Promotes Parkin-Independent Mitophagy in the Drosophila Brain and in Human Neurons (2023) · cites this paper as [19]
USP8 levels seem inversely correlated with the extent of Lewy Body ubiquitination in post-mortem brains of PD patients.
“Moreover, its levels seem to be inversely correlated with the extent of Lewy Body (LB) ubiquitination in post-mortem brains of PD patients [19].”
From USP8 Down-Regulation Promotes Parkin-Independent Mitophagy in the Drosophila Brain and in Human Neurons (2023) · cites this paper as [19]
In this work, we show that we can enhance autophagy and mitophagy by down-regulating USP8, a DUB that is upregulated in age-related neurodegenerative conditions.
“In summary, in this work we show that we can enhance autophagy and mitophagy by down-regulating USP8, a DUB that is upregulated in age-related neurodegenerative conditions [19,42].”
From USP8 Down-Regulation Promotes Parkin-Independent Mitophagy in the Drosophila Brain and in Human Neurons (2023) · cites this paper as [19]
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Diagnosis and management of dementia with Lewy bodies: Third report of the DLB consortium
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Chaperone Suppression of α-Synuclein Toxicity in a Drosophila Model for Parkinson's Disease
Auluck, P. K., Chan, H. Y. E., Trojanowski, J. Q., Lee, V. M.-Y., & Bonini, N. M. (2002) · Science · doi:10.1126/science.1067389 · Cited by 1,227
Molecular mechanism of multivesicular body biogenesis by ESCRT complexes
Wollert, T., & Hurley, J. H. (2010) · Nature · doi:10.1038/nature08849 · Cited by 804
Phosphorylated α-Synuclein Is Ubiquitinated in α-Synucleinopathy Lesions
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Manecka, D.-L., Vanderperre, B., Fon, E. A., & Durcan, T. M. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00311 · Cited by 21
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Metadata
- Authors
- Alexopoulou, Z., Lang, J., Perrett, R. M., Elschami, M., Hurry, M. E. D., Kim, H. T., Mazaraki, D., Szabo, A., Kessler, B. M., Goldberg, A. L., Ansorge, O., Fulga, T. A., & Tofaris, G. K.
- Affiliations
- Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom;
- Department of Cell Biology, Harvard Medical School, Boston, MA 02115;
- Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, United Kingdom;
- Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, United Kingdom
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2016-07-21
- Volume
- 113
- Issue
- 32
- ISSN
- 0027-8424
- 1091-6490
- Cited by
- 125
- References
- 5
- Language
- en
- Funders
- Wellcome Trust (97479/Z/11/X)
- Oxford Biomedical Research Centre (N/A)
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