ArticleProceedings of the National Academy of Sciences of the United States of America2013
Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 116 papers, 1 of them a synthesis that pooled it.
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Who cites it
116 citing papers in PubMed, 1 synthesis or guideline pooled it, 188 citations in OpenAlex.
- Targeting Ubiquitin-Proteasome Pathway by Natural Products: Novel Therapeutic Strategy for Treatment of Neurodegenerative Diseases.Frontiers in physiology · 2020Pooled it
- Safety, Immunovirologic, and Central Nervous System Effects of PD-1 Inhibition in People With HIV Without Malignancy.The Journal of infectious diseases · 2026Article
- Early Retinal UCHL1 Dysregulation Coupled With Synaptic Loss Reflects Alzheimer's Disease Severity.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Tightly Knotted Enzymes Inhibit Protein-Protein Aggregation.bioRxiv : the preprint server for biology · 2026Article
- Variant-to-gene mapping identifiesbioRxiv : the preprint server for biology · 2026Article
- Identification of myokymia in adult-onset hereditary spastic paraplegia type 79A: Implications for the phenotypic spectrum.eNeurologicalSci · 2026Article
- Synergistic retinal UCHL1 dysregulation and synaptic vulnerability reflect Alzheimer's disease severity.bioRxiv : the preprint server for biology · 2026Article
- Potential Anti-Cancer Drug 6RK73 Suppresses Ovarian Cancer Growth by Inactivating the AKT1/Sp1 Induced c-Myc Signaling Pathway.Journal of Cancer · 2026Article
- A new variant in the UCHL1 gene supporting its implication in late-onset ataxia with optic atrophy.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2025Article
- Ubiquitination in the Nervous System: From Molecular Mechanisms to Disease Implications.Molecular neurobiology · 2025Review
- Article
- Carbonic Anhydrase Inhibition Sensitizes Group 3 Medulloblastoma to Radiotherapy.Cancer research · 2025Article
- UCH-L1 in Alzheimer's Disease: A Crucial Player in Dementia-Associated Mechanisms.International journal of molecular sciences · 2025Review
- Ubiquitin C-Terminal Hydrolase L1 (UCHL1), Beyond Hydrolysis.BioEssays : news and reviews in molecular, cellular and developmental biology · 2025Review
- The relevance of combined testing of cerebrospinal fluid glial fibrillary acidic protein and ubiquitin C-terminal hydrolase L1 in multiple sclerosis and peripheral neuropathy.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2025Article
- Elevated Cerebrospinal Fluid Ubiquitin Carboxyl-Terminal Hydrolase Isozyme L1 in Asymptomatic C9orf72 Hexanucleotide Repeat Expansion Carriers.Annals of neurology · 2025Observational
- Integrating machine learning for the identification of ubiquitination-associated genes in moyamoya disease.Frontiers in neurology · 2025Article
- Exploring the role of ubiquitination modifications in migraine headaches.Frontiers in immunology · 2025Review
- Scalable Thiol Reactivity Profiling Identifies Azetidinyl Oxadiazoles as Cysteine-Targeting Electrophiles.Journal of the American Chemical Society · 2024Article
- Abolishing UCHL1's hydrolase activity exacerbates ischemia-induced axonal injury and functional deficits in mice.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2024Article
56 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
21 authors at 9 institutions in 5 countries.
Funding
Abstract
Ubiquitin C-terminal hydrolase-L1 (UCHL1), a neuron-specific de-ubiquitinating enzyme, is one of the most abundant proteins in the brain. We describe three siblings from a consanguineous union with a previously unreported early-onset progressive neurodegenerative syndrome featuring childhood onset blindness, cerebellar ataxia, nystagmus, dorsal column dysfuction, and spasticity with upper motor neuron dysfunction. Through homozygosity mapping of the affected individuals followed by whole-exome sequencing of the index case, we identified a previously undescribed homozygous missense mutation within the ubiquitin binding domain of UCHL1 (UCHL1(GLU7ALA)), shared by all affected subjects. As demonstrated by isothermal titration calorimetry, purified UCHL1(GLU7ALA), compared with WT, exhibited at least sevenfold reduced affinity for ubiquitin. In vitro, the mutation led to a near complete loss of UCHL1 hydrolase activity. The GLU7ALA variant is predicted to interfere with the substrate binding by restricting the proper positioning of the substrate for tunneling underneath the cross-over loop spanning the catalytic cleft of UCHL1. This interference with substrate binding, combined with near complete loss of hydrolase activity, resulted in a >100-fold reduction in the efficiency of UCHL1(GLU7ALA) relative to WT. These findings demonstrate a broad requirement of UCHL1 in the maintenance of the nervous system.
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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.