Редактирование: UCHL1 (раздел)

==Publications==

{{medline-entry
|title=Abolishing [[UCHL1]]'s hydrolase activity exacerbates TBI-induced axonal injury and neuronal death in mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33159930
|abstract=Ubiquitin (Ub) C-terminal hydrolase L1 ([[UCHL1]]) is a multifunctional protein that is expressed in neurons throughout brain at high levels. [[UCHL1]] deletion is associated with axonal degeneration, progressive sensory motor ataxia, and premature death in mice. [[UCHL1]] has been hypothesized to play a role in the pathogenesis of neurodegenerative diseases and recovery after neuronal injury. [[UCHL1]] hydrolyzes Ub from polyubiquitinated (poly-Ub) proteins, but also may ligate Ub to select neuronal proteins, and interact with cytoskeletal proteins. These and other mechanisms have been hypothesized to underlie [[UCHL1]]'s role in neurodegeneration and response to brain injury. A [[UCHL1]] knockin mouse containing a C90A mutation (C90A) devoid of hydrolase activity was constructed. The C90A mouse did not develop the sensory and motor deficits, degeneration of the gracile nucleus and tract, or premature death as seen in [[UCHL1]] deficient mice. C90A and wild type (WT) mice were subjected to the controlled cortical impact (CCI) model of traumatic brain injury (TBI), and cell death, axonal injury and behavioral outcome were assessed. C90A mice exhibited decreased spared tissue volume, greater loss of [[CA1]] hippocampal neurons and greater axonal injury as detected using anti-amyloid precursor protein (APP) antibody and anti- non-phosphorylated neurofilament H (SMI-32) antibody immunohistochemistry after CCI compared to WT controls. Poly-Ub proteins and Beclin-1 were elevated after CCI in C90A mice compared to WT controls. Vestibular motor deficits assessed using the beam balance test resolved by day 5 after CCI in WT mice but not in C90A mice. These results suggest that the hydrolase activity of [[UCHL1]] does not account for the progressive neurodegeneration and premature death seen in mice that do not express full length [[UCHL1]]. The hydrolase activity of [[UCHL1]] contributes to the function of the ubiquitin proteasome pathway (UPP), ameliorates activation of autophagy, and improves motor recovery after CCI. Thus, [[UCHL1]] hydrolase activity plays an important role in acute injury response after TBI.

|keywords=* Aging
* Axonal injury
* Neurodegeneration
* Traumatic brain injury
* Ubiquitin carboxy terminal hydrolase L1
* Ubiquitin proteasome pathway
|full-text-url=https://sci-hub.do/10.1016/j.expneurol.2020.113524
}}
{{medline-entry
|title=FAM96B inhibits the senescence of dental pulp stem cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32039527
|abstract=Dental pulp stem cells (DPSCs) are considered a remarkable source for the regeneration of dental pulp tissues, but their therapeutic effectiveness remains limited, especially in elderly people. Previous studies found that senescence has a negative effect on the proliferation and differentiation potential of DPSCs. Moreover, numerous long non-coding RNA (lncRNA) and messenger RNA were significantly differentially regulated in DPSCs from young and elderly donors. However, the changes in DPSCs protein during senescence have not been addressed. In this study, differences in DPSC protein expression profiles and coexpression of protein and lncRNA were analyzed using proteomics and bioinformatics. The results showed 75 upregulated proteins and 69 downregulated proteins in DPSCs from elderly donors. Vasopressin-regulated water reabsorption, Parkinson's disease, Alzheimer's disease, and protein export were the top four functional pathways associated with DPSCs. High mobility group N1 (HMGN1), [[HMGN2]], [[UCHL1]], and the family with sequence similarity 96 member B homeobox gene (FAM96B) were associated with DPSCs senescence. Then, we investigated FAM96B function in DPSCs. After FAM96B depletion, telomerase reverse transcriptase ([[TERT]]) activity decreased, but the number of senescence-associated β-galactosidase (SA-β-gal) positive cells and the protein levels of p16, p53 were significantly increased. Gain-of-function assays suggested that FAM96B overexpression was positively correlated with [[TERT]] activity, but negatively correlated with the number of SA-β-gal positive cells and the protein levels of P16 and P53. Moreover, after FAM96B overexpression, the results showed a significant increase in alkaline phosphatase activity and an enhanced mineralization ability of DPSCs. The reverse-transcription polymerase chain reaction results also showed that dentin sialophosphoprotein and osteocalcin were expressed at greater levels. The carboxyfluorescein succinimidyl ester (CFSE) results displayed that FAM96B increased the proliferation potential of DPSCs. Our study revealed candidate proteins that might be related to DPSCs senescence and provided information to elucidate the mechanism of the biological changes in DPSCs' aging. Moreover, FAM96B was demonstrated to play an important role in suppressing DPSCs senescence and promoting osteogenic differentiation and proliferation.

|keywords=* FAM96B
* aging
* dental pulp stem cells (DPSCs)
* proteomic analysis
|full-text-url=https://sci-hub.do/10.1002/cbin.11319
}}
{{medline-entry
|title=Role of the Ubiquitin C-Terminal Hydrolase L1-Modulated Ubiquitin Proteasome System in Auditory Cortex Senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28407635
|abstract=According to recent studies, central auditory impairments are closely related to neurodegenerative diseases. However, the mechanism of central presbycusis remains unclear. Ubiquitin C-terminal hydrolase L1 ([[UCHL1]]) is important in maintaining proteasomal activity; however, the detailed mechanism has not yet been fully elucidated. This study aims to investigate the molecular alterations involved in [[UCHL1]] regulation during auditory cortex aging. D-Galactose (D-gal) induces oxidative stress and senescence in the auditory cortex, as reported in our previous studies. Primary auditory cortex cells were treated with D-gal for 72 h or 5 days. The proteins related to the ubiquitin proteasome system (UPS) and proteasomal activities were evaluated. [[UCHL1]] was overexpressed, and the effects of [[UCHL1]] on the UPS and proteasomal activity were analyzed. Proteasomal activity was elevated at 72 h and decreased at 5 days in D-gal-treated primary auditory cortex cells. We also found that overexpression of [[UCHL1]] increased the UPS-related proteins UBE1, [[PSMA7]], ubiquitinated proteins, and monoubiquitin, and proteasomal activity. The results suggest that [[UCHL1]] may modify the aging process in the auditory cortex by regulating UPS- related proteins.
|mesh-terms=* Aging
* Analysis of Variance
* Animals
* Auditory Cortex
* Biomarkers
* Blotting, Western
* Cells, Cultured
* Disease Models, Animal
* Random Allocation
* Rats
* Rats, Sprague-Dawley
* Reactive Oxygen Species
* Sensitivity and Specificity
* Ubiquitin Thiolesterase
|keywords=* Aging
* PSMA7
* Proteasome
* UBE1
* Ubiquitin
|full-text-url=https://sci-hub.do/10.1159/000468944
}}
{{medline-entry
|title=Life and death in the trash heap: The ubiquitin proteasome pathway and [[UCHL1]] in brain aging, neurodegenerative disease and cerebral Ischemia.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27702698
|abstract=The ubiquitin proteasome pathway (UPP) is essential for removing abnormal proteins and preventing accumulation of potentially toxic proteins within the neuron. UPP dysfunction occurs with normal aging and is associated with abnormal accumulation of protein aggregates within neurons in neurodegenerative diseases. Ischemia disrupts UPP function and thus may contribute to UPP dysfunction seen in the aging brain and in neurodegenerative diseases. Ubiquitin carboxy-terminal hydrolase L1 ([[UCHL1]]), an important component of the UPP in the neuron, is covalently modified and its activity inhibited by reactive lipids produced after ischemia. As a result, degradation of toxic proteins is impaired which may exacerbate neuronal function and cell death in stroke and neurodegenerative diseases. Preserving or restoring [[UCHL1]] activity may be an effective therapeutic strategy in stroke and neurodegenerative diseases.
|mesh-terms=* Aging
* Animals
* Brain
* Brain Ischemia
* Humans
* Neurodegenerative Diseases
* Neurons
* Proteasome Endopeptidase Complex
* Ubiquitin
* Ubiquitin Thiolesterase
|keywords=* Aging
* Cerebral ischemia
* Neurodegenerative disease
* Ubiquitin
* Ubiquitin carboxy-terminal hydrolase L1(UCHL1)
* Ubiquitin proteasome pathway (UPP)
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5250550
}}
{{medline-entry
|title=Amelioration of neuronal cell death in a spontaneous obese rat model by dietary restriction through modulation of ubiquitin proteasome system.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27260470
|abstract=Dietary restriction (DR) has been shown to increase longevity, delay onset of aging, reduce DNA damage and oxidative stress and prevent age-related decline of neuronal activity. We previously reported the role of altered ubiquitin proteasome system (UPS) in the neuronal cell death in a spontaneous obese rat model (WNIN/Ob rat). In this study, we investigated the effect of DR on obesity-induced neuronal cell death in a rat model. Two groups of 40-day-old WNIN/Ob rats were either fed ad libitum (Ob) or pair-fed with lean. The lean phenotype of WNIN/Ob rats served as ad libitum control. These animals were maintained for 6.5months on their respective diet regime. At the end of the study, cerebral cortex was collected and markers of UPS, endoplasmic reticulum (ER) stress and autophagy were analyzed by quantitative real-time polymerase chain reaction, immunoblotting and immunohistochemistry. Chymotrypsin-like activity of proteasome was assayed by the fluorimetric method. Apoptotic cells were analyzed by TUNEL assay. DR improved metabolic abnormalities in obese rats. Alterations in UPS (up-regulation of [[UCHL1]], down-regulation of [[UCHL5]], declined proteasomal activity), increased ER stress, declined autophagy and increased expression of α-synuclein, p53 and [[BAX]] were observed in obese rats and DR alleviated these changes in obese rats. Further, DR decreased TUNEL-positive cells. In conclusion, DR in obese rats could not only restore the metabolic abnormalities but also preserved neuronal health in the cerebral cortex by preventing alterations in the UPS.
|mesh-terms=* Aging
* Animals
* Apoptosis
* Autophagy
* Biomarkers
* Caloric Restriction
* Cerebral Cortex
* Endoplasmic Reticulum Stress
* Gene Expression Regulation, Developmental
* Nerve Tissue Proteins
* Neurodegenerative Diseases
* Neurons
* Neuroprotection
* Obesity
* Proteasome Endopeptidase Complex
* Rats, Mutant Strains
* Tumor Suppressor Protein p53
* Ubiquitination
* alpha-Synuclein
* bcl-2-Associated X Protein
|keywords=* Apoptosis
* Dietary restriction
* ER stress
* Neurodegeneration
* Ubiquitin proteasome system
* obesity
|full-text-url=https://sci-hub.do/10.1016/j.jnutbio.2016.03.008
}}
{{medline-entry
|title=Effect of age on expression of spermatogonial markers in bovine testis and isolated cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27180120
|abstract=Spermatogonial stem cells (SSC) are the most undifferentiated germ cell present in adult male testes and, it is responsible to maintain the spermatogenesis. Age has a negative effect over stem cell, but the aging effect on SSC is not elucidated for bovine. The present study aim to evaluate the effect of age on the expression of undifferentiated spermatogonial markers in testis and in enriched testicular cells from prepubertal calves and adult bulls. In this matter, testicular parenchyma from calves (3-5 months) (n=5) and bulls with 3 years of age (n=5) were minced and, isolated cells were obtained after two enzymatic digestions. Differential platting was performed for two hours onto BSA coated dish. Cell viability was assessed by Trypan Blue solution exclusion method and testicular cells enriched for SSC was evaluated by expression of specific molecular markers by qRT-PCR (POU5F1, [[GDNF]], [[CXCR4]], [[UCHL1]], ST3GAL, [[SELP]], [[ICAM1]] and ITGA6) and flow cytometry (GFRA1, [[CXCR4]] and ITGA6). [[CXCR4]] and [[UCHL1]] expression was evaluated in fixated testes by immunohistochemistry. We observed that age just affected the expression of selective genes [[[SELP]] (Fold Change=5.61; p=0.0023) and [[UCHL1]] (Fold Change=4.98; p=0.0127)]. By flow cytometry, age affected only the proportion of ITGA6  cells (P<0.001), which was higher in prepubertal calves when compared to adult bulls. In situ, we observed an effect of age on the number of [[UCHL1]]  (p=0.0006) and [[CXCR4]]  (p=0.0139) cells per seminiferous tubule. At conclusion, age affects gene expression and the population of cells expressing specific spermatogonial markers in the bovine testis. 
|mesh-terms=* Aging
* Animals
* Biomarkers
* Cattle
* Flow Cytometry
* Gene Expression Regulation
* Male
* Reverse Transcriptase Polymerase Chain Reaction
* Sexual Maturation
* Spermatogonia
* Testis
|keywords=* Age and undifferentiated germ cell
* Bovine
* Markers
* Spermatogonia
|full-text-url=https://sci-hub.do/10.1016/j.anireprosci.2016.04.004
}}
{{medline-entry
|title=It Is All about (U)biquitin: Role of Altered Ubiquitin-Proteasome System and [[UCHL1]] in Alzheimer Disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26881020
|abstract=Free radical-mediated damage to macromolecules and the resulting oxidative modification of different cellular components are a common feature of aging, and this process becomes much more pronounced in age-associated pathologies, including Alzheimer disease (AD). In particular, proteins are particularly sensitive to oxidative stress-induced damage and these irreversible modifications lead to the alteration of protein structure and function. In order to maintain cell homeostasis, these oxidized/damaged proteins have to be removed in order to prevent their toxic accumulation. It is generally accepted that the age-related accumulation of "aberrant" proteins results from both the increased occurrence of damage and the decreased efficiency of degradative systems. One of the most important cellular proteolytic systems responsible for the removal of oxidized proteins in the cytosol and in the nucleus is the proteasomal system. Several studies have demonstrated the impairment of the proteasome in AD thus suggesting a direct link between accumulation of oxidized/misfolded proteins and reduction of this clearance system. In this review we discuss the impairment of the proteasome system as a consequence of oxidative stress and how this contributes to AD neuropathology. Further, we focus the attention on the oxidative modifications of a key component of the ubiquitin-proteasome pathway, [[UCHL1]], which lead to the impairment of its activity. 
|mesh-terms=* Adenosine Triphosphate
* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Animals
* Cell Nucleus
* Cytosol
* Homeostasis
* Humans
* Mice
* Mutation
* Oxidation-Reduction
* Oxidative Stress
* Oxygen
* Proteasome Endopeptidase Complex
* Protein Denaturation
* Protein Folding
* Ubiquitin
* Ubiquitin Thiolesterase

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4736377
}}
{{medline-entry
|title=Loss of [[UCHL1]] promotes age-related degenerative changes in the enteric nervous system.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24994982
|abstract=[[UCHL1]] (ubiquitin carboxyterminal hydrolase 1) is a deubiquitinating enzyme that is particularly abundant in neurons. From studies of a spontaneous mutation arising in a mouse line it is clear that loss of function of [[UCHL1]] generates profound degenerative changes in the central nervous system, and it is likely that a proteolytic deficit contributes to the pathology. Here these effects were found to be recapitulated in mice in which the Uchl1 gene had been inactivated by homologous recombination. In addition to the previously documented neuropathology associated with loss of [[UCHL1]] function, axonal swellings were detected in the striatum. In agreement with previously reported findings the loss of [[UCHL1]] function was accompanied by perturbations in ubiquitin pools, but glutathione levels were also significantly depleted in the brains of the knockout mice, suggesting that oxidative defense mechanisms may be doubly compromised. To determine if, in addition to its role in the central nervous system, [[UCHL1]] function is also required for homeostasis of the enteric nervous system the gastrointestinal tract was analyzed in [[UCHL1]] knockout mice. The mice displayed functional changes and morphological changes in gut neurons that preceded degenerative changes in the brain. The changes were qualitatively and quantitatively similar to those observed in wild type mice of much greater age, and strongly resemble changes reported for elderly humans. [[UCHL1]] knockout mice should therefore serve as a useful model of gut aging. 

|keywords=* aging
* deubiquitinating enzyme
* enteric nervous system
* glutathione
* ubiquitin
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4063237
}}