Ubiquitin C-terminal hydrolase L1 (UCH-L1): structure, distribution and roles in brain function and dysfunction

Bishop, Paul; Rocca, Dan L.; Henley, Jeremy M.

doi:10.1042/bcj20160082

Cited by 206 publications

(178 citation statements)

References 108 publications

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“…UCHL1 is a ubiquitin-protein hydrolase that cleaves the C-terminal glycine of ubiquitin during the processing of ubiquitin precursors and of ubiquitinated proteins, thus restoring free ubiquitin pools (Bishop et al, 2016). Loss-of-function UCHL1 mutations causes several neurodegenerative diseases that result in increased mortality including familial Parkinson’s disease (PARK5), childhood neurodegeneration, and spinal gracile axonal dystrophy.…”

Section: Discussionmentioning

confidence: 99%

Rare Disease Mechanisms Identified by Genealogical Proteomics of Copper Homeostasis Mutant Pedigrees

et al. 2018

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Rare neurological diseases shed light onto universal neurobiological processes. However, molecular mechanisms connecting genetic defects to their disease phenotypes are elusive. Here, we obtain mechanistic information by comparing proteomes of cells from individuals with rare disorders with proteomes from their disease-free consanguineous relatives. We use triple-SILAC mass spectrometry to quantify proteomes from human pedigrees affected by mutations in ATP7A, which cause Menkes disease, a rare neurodegenerative and neurodevelopmental disorder stemming from systemic copper depletion. We identified 214 proteins whose expression was altered in ATP7A fibroblasts. Bioinformatic analysis of ATP7A-mutant proteomes identified known phenotypes and processes affected in rare genetic diseases causing copper dyshomeostasis, including altered mitochondrial function. We found connections between copper dyshomeostasis and the UCHL1/PARK5 pathway of Parkinson disease, which we validated with mitochondrial respiration and Drosophila genetics assays. We propose that our genealogical "omics" strategy can be broadly applied to identify mechanisms linking a genomic locus to its phenotypes.

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Section: Discussionmentioning

confidence: 99%

Rare Disease Mechanisms Identified by Genealogical Proteomics of Copper Homeostasis Mutant Pedigrees

et al. 2018

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“…Another group developed the first described fluorometric cell lysatebased assay to mirror physiological conditions for small molecule screens (Ott et al, 2017). They targeted UCHL1, a DUB that is overexpressed in many cancers (Bishop, Rocca, & Henley, 2016), as a proof of principle for developing DUB inhibitors with a cell lysate-based assay that they called AlphaLISA (Ott et al, 2017). HA-tagged UCHL1 was labeled with an alpha-streptavidin donor bead and probed with biotin-tagged Ub.…”

Section: Activity-based Small Molecule Screens For Ups Inhibitorsmentioning

confidence: 99%

Emerging drug development technologies targeting ubiquitination for cancer therapeutics

Veggiani

Gerpe

Sidhu

et al. 2019

Pharmacology & Therapeutics

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a b s t r a c t a r t i c l e i n f o Development of effective cancer therapeutic strategies relies on our ability to interfere with cellular processes that are dysregulated in tumors. Given the essential role of the ubiquitin proteasome system (UPS) in regulating a myriad of cellular processes, it is not surprising that malfunction of UPS components is implicated in numerous human diseases, including many types of cancer. The clinical success of proteasome inhibitors in treating multiple myeloma has further stimulated enthusiasm for targeting UPS proteins for pharmacological intervention in cancer treatment, particularly in the precision medicine era. Unfortunately, despite tremendous efforts, the paucity of potent and selective UPS inhibitors has severely hampered attempts to exploit the UPS for therapeutic benefits. To tackle this problem, many groups have been working on technology advancement to rapidly and effectively screen for potent and specific UPS modulators as intracellular probes or early-phase therapeutic agents. Here, we review several emerging technologies for developing chemical-and protein-based molecules to manipulate UPS enzymatic activity, with the aim of providing an overview of strategies available to target ubiquitination for cancer therapy.

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“…5 Ubiquitin C-terminal hydrolase L1 (UCH-L1) is a neuron-specific enzyme that is highly abundant in the brain. 6 UCH-L1 is a deubiquitinating enzyme that is required for normal cognitive function. 7,8 UCH-L1 has been implicated in the pathophysiology of Parkinson's disease (PD), 9 Alzheimer's disease (AD), 10 Huntington's disease, 11 and epileptic seizures.…”

Section: Introductionmentioning

confidence: 99%

Serum ubiquitin C‐terminal hydrolase L1 predicts cognitive impairment in patients with acute organophosphorus pesticide poisoning

Pang

Liu

et al. 2019

Clinical Laboratory Analysis

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BackgroundTo assess the usefulness of serum C‐terminal hydrolase L1 (UCH‐L1) level as a biomarker for predicting cognitive impairment in patients with acute organophosphorus pesticide poisoning (AOPP).MethodsTwo hundred and seven adult patients with AOPP were included in this study. Serum UCH‐L1 levels were assessed on admission (Day 1 postpoisoning) and on Days 3 and 7 postpoisoning. The associations between serum UCH‐L1 levels, other clinical predictors, and cognitive function evaluated on Day 30 postpoisoning were investigated.ResultsOn multivariate analysis, serum UCH‐L1 levels on admission (odds ratio [OR] 1.889, 95% confidence interval [CI] 1.609‐3.082, P = 0.002) and 24‐hour APACHE II score (OR 1.736, 95% CI 1.264‐3.272, P = 0.012) were independent predictors of cognitive impairment on Day 30 postpoisoning. Based on the receiver operating characteristic curve, serum UCH‐L1 levels >5.9 ng/mL on admission predicted cognitive impairment on Day 30 postpoisoning with 86.1% sensitivity and 72.5% specificity (area under the curve, 0.869; 95% CI 0.815‐0.923). On admission [8.51 (6.53‐10.22) ng/mL vs 4.25 (2.57‐6.31) ng/mL, P < 0.001] and Day 3 [9.31 (7.92‐10.98) ng/mL vs 3.32 (2.25‐5.13) ng/mL, P < 0.001] and Day 7 [4.96 (3.28‐7.26) ng/mL vs 2.27 (1.55‐3.24) ng/mL, P < 0.001] postpoisoning, serum UCH‐L1 concentration was significantly higher in patients that developed cognitive impairment compared to those that did not.ConclusionThis study demonstrates that serum UCH‐L1 level has potential as a novel biomarker for predicting cognitive impairment 30 days after AOPP.

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Ubiquitin C-terminal hydrolase L1 (UCH-L1): structure, distribution and roles in brain function and dysfunction

Cited by 206 publications

References 108 publications

Rare Disease Mechanisms Identified by Genealogical Proteomics of Copper Homeostasis Mutant Pedigrees

Rare Disease Mechanisms Identified by Genealogical Proteomics of Copper Homeostasis Mutant Pedigrees

Emerging drug development technologies targeting ubiquitination for cancer therapeutics

Serum ubiquitin C‐terminal hydrolase L1 predicts cognitive impairment in patients with acute organophosphorus pesticide poisoning

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