ArticleProceedings of the National Academy of Sciences of the United States of America2016
Deubiquitinase Usp8 regulates α-synuclein clearance and modifies its toxicity in Lewy body disease.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 81 papers, 1 of them a synthesis that pooled it.
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Who cites it
81 citing papers in PubMed, 1 synthesis or guideline pooled it, 126 citations in OpenAlex.
- The Emerging Roles of E3 Ligases and DUBs in Neurodegenerative Diseases.Molecular neurobiology · 2023Pooled it
- Decode the Ubiquitinome in Parkinson's Disease: From Pathological Aggregates to Targeted DUB Therapeutics.Neuroscience bulletin · 2026Review
- Systemic and cardiac pathology induced by a clinically relevant USP8 activating mutation.Disease models & mechanisms · 2026Article
- Ubiquitin-specific peptidase-19 links TDP-43 aggregation to ER stress.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Deubiquitinase USP8 regulates the spindle assembly checkpoint in oocytes.Science advances · 2026Article
- Deubiquitinating enzymes at the crossroads of blood-brain barrier integrity and neurodegeneration: mechanistic insights, therapeutic targeting and future directions.Tissue barriers · 2026Review
- Ubiquitin signatures on aggregating proteins in neurodegeneration.Essays in biochemistry · 2025Review
- Co-expression-wide association studies link genetically regulated interactions with complex traits.Nature communications · 2025Article
- Deubiquitinating enzymes in parkinson's disease: molecular mechanisms and therapeutic potential.Molecular medicine (Cambridge, Mass.) · 2025Review
- Elucidation of short linear motif-based interactions of the MIT and rhodanese domains of the ubiquitin-specific protease 8.Biology direct · 2025Article
- The Co-Delivery of Natural Products and Small RNAs for Cancer Therapy: A Review.Molecules (Basel, Switzerland) · 2025Review
- Aspirin inhibits proteasomal degradation and promotes α-synuclein aggregate clearance through K63 ubiquitination.Nature communications · 2025Article
- OTUD5 Protects Dopaminergic Neurons by Promoting the Degradation of α-Synuclein in Parkinson's Disease Model.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Molecular Symphony of Mitophagy: Ubiquitin-Specific Protease-30 as a Maestro for Precision Management of Neurodegenerative Diseases.CNS neuroscience & therapeutics · 2025Review
- Posttranslational Modifications ofPharmacological reviews · 2024Review
- The role of ubiquitination in health and disease.MedComm · 2024Review
- Protein modification in neurodegenerative diseases.MedComm · 2024Review
- Therapeutic Implications and Regulations of Protein Post-translational Modifications in Parkinsons Disease.Cellular and molecular neurobiology · 2024Review
- Exploring the Role of Ubiquitin-Proteasome System in the Pathogenesis of Parkinson's Disease.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Review
21 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 4 institutions in 2 countries.
Funding
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.
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