ArticleProceedings of the National Academy of Sciences of the United States of America2011
α-Synuclein fate is determined by USP9X-regulated monoubiquitination.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 114 papers, 1 of them a synthesis that pooled it.
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Who cites it
114 citing papers in PubMed, 1 synthesis or guideline pooled it, 174 citations in OpenAlex.
- The Emerging Roles of E3 Ligases and DUBs in Neurodegenerative Diseases.Molecular neurobiology · 2023Pooled it
- The role of E3 ubiquitin ligases in selective types of macroautophagy.EMBO reports · 2026Review
- Decode the Ubiquitinome in Parkinson's Disease: From Pathological Aggregates to Targeted DUB Therapeutics.Neuroscience bulletin · 2026Review
- The Progress of Active Immunotherapy for Parkinson's Disease.International journal of molecular sciences · 2026Review
- Breaking the proteasome balance: α-synuclein and the ubiquitin-proteasome system.Frontiers in cell and developmental biology · 2026Review
- 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
- Ubiquitin-Specific Protease 20 Promotes CCCP-Induced Mitophagy Through Deubiquitination and Stabilization of Serine/Threonine Protein Kinase PINK1.Journal of molecular neuroscience : MN · 2025Article
- Benchmarking In-Cell Proteomics for Profiling Neuroblastoma Cell Differentiation and the Ubiquitin-Proteasome System.Journal of proteome research · 2025Article
- Deubiquitinating enzymes in parkinson's disease: molecular mechanisms and therapeutic potential.Molecular medicine (Cambridge, Mass.) · 2025Review
- OTUD5 Protects Dopaminergic Neurons by Promoting the Degradation of α-Synuclein in Parkinson's Disease Model.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Macrophage-derived KIF13B interacts with USP9X to attenuate abdominal aortic aneurysm development by potentiating TFEB stability.Theranostics · 2025Article
- Article
- Nrf1 acts as a highly-conserved determinon for maintaining robust redox homeostasis in the eco-evo-devo process of life histories.Cell stress · 2025Review
- Posttranslational Modifications ofPharmacological reviews · 2024Review
- Article
- Exploring the Role of Ubiquitin-Proteasome System in the Pathogenesis of Parkinson's Disease.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Review
- Decoding Ubiquitin Modifications by Mass Spectrometry.Advances in experimental medicine and biology · 2024Review
- USP19 deubiquitinase inactivation regulates α-synuclein ubiquitination and inhibits accumulation of Lewy body-like aggregates in mice.NPJ Parkinson's disease · 2023Article
54 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.