ArticleNPJ Parkinson's disease2023
USP19 deubiquitinase inactivation regulates α-synuclein ubiquitination and inhibits accumulation of Lewy body-like aggregates in mice.
Article in NPJ Parkinson's disease, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 16 citations in OpenAlex.
- Deletion or immunotherapeutic blockade of FcγRIIb (CD32b) impairs α-Syn propagation in vivo.Acta neuropathologica · 2026Article
- Decode the Ubiquitinome in Parkinson's Disease: From Pathological Aggregates to Targeted DUB Therapeutics.Neuroscience bulletin · 2026Review
- Effect of inactivation of the USP19 deubiquitinase gene in mice on important phenotypes of aging.The journals of gerontology. Series A, Biological sciences and medical sciences · 2026Article
- YY1 Transcriptionally Activates USP19 to Mediate TRAF6 Deubiquitination to Promote Microglial Inflammation and M1 Polarization in Depression Development.Neurochemical research · 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
- Population-scale burden analysis of rare damaging coding variants identifies novel risk genes for Alzheimer's disease and Parkinson's disease.medRxiv : the preprint server for health sciences · 2026Article
- USP19 restores mitochondrial function in neurons by deubiquitinating FUS to alleviate trigeminal neuralgia.Experimental brain research · 2025Article
- Deubiquitinating enzymes in parkinson's disease: molecular mechanisms and therapeutic potential.Molecular medicine (Cambridge, Mass.) · 2025Review
- Development of a genetically encoded melanocortin sensor for high sensitivity in vivo imaging.Molecular metabolism · 2025Article
- Lysophosphatidylcholine promoting α-Synuclein aggregation in Parkinson's disease: disrupting GCase glycosylation and lysosomal α-Synuclein degradation.NPJ Parkinson's disease · 2025Article
- Enhanced secretion of the amyotrophic lateral sclerosis ALS-associated misfolded TDP-43 mediated by the ER-ubiquitin specific peptidase USP19.Cellular and molecular life sciences : CMLS · 2025Article
- Mono-UFMylation promotes misfolding-associated secretion of α-synuclein.Science advances · 2024Article
- Emerging role of microglia in inter-cellular transmission of α-synuclein in Parkinson's disease.Frontiers in aging neuroscience · 2024Review
- Review
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Authors and funding
20 authors at 3 institutions in 2 countries.
Funding
Abstract
The USP19 deubiquitinase is found in a locus associated with Parkinson's Disease (PD), interacts with chaperonins, and promotes secretion of α-synuclein (α-syn) through the misfolding-associated protein secretion (MAPS) pathway. Since these processes might modulate the processing of α-syn aggregates in PD, we inactivated USP19 (KO) in mice expressing the A53T mutation of α-syn and in whom α-syn preformed fibrils (PFF) had been injected in the striatum. Compared to WT, KO brains showed decreased accumulation of phospho-synuclein (pSyn) positive aggregates. This improvement was associated with less activation of microglia and improved performance in a tail-suspension test. Exposure of primary neurons from WT and KO mice to PFF in vitro also led to decreased accumulation of pSyn aggregates. KO did not affect uptake of PFF nor propagation of aggregates in the cultured neurons. We conclude that USP19 instead modulates intracellular dynamics of aggregates. At an early time following PFF injection when the number of pSyn-positive neurons were similar in WT and KO brains, the KO neurons contained less aggregates. KO brain aggregates stained more intensely with anti-ubiquitin antibodies. Immunoprecipitation of soluble proteins from WT and KO brains with antibodies to pSyn showed higher levels of ubiquitinated oligomeric species in the KO samples. We propose that the improved pathology in USP19 KO brains may arise from decreased formation or enhanced clearance of the more ubiquitinated aggregates and/or enhanced disassembly towards more soluble oligomeric species. USP19 inhibition may represent a novel therapeutic approach that targets the intracellular dynamics of α-syn complexes.
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Registered trials
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.