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Change in UCH-L1 expression pattern in the developing mouse brain. Cryosections of the brain at E14 and E16 were double stained with UCH-L1 and the neural progenitor marker nestin (A) or early neuronal marker TuJ1 (B). Unlike with UCH-L1, staining patterns for TuJ1 and nestin do not change between E14 and E16. At E14, UCH-L1 expression is higher in the VZ than in the MZ. At E16, higher expression of UCH-L1 is reciprocally detected in the CP. By contrast, at both E14 and E16, nestin is highly expressed in the VZ, and TuJ1 expression is higher in the MZ/CP. Fluorescence intensities per field (1700 m 2 ) were measured in each layer of the E14 and E16 brain and are shown to the right. Bars, 80 m. (C,D) Higher-magnification images from A,B of UCH-L1 expression in the E14 and E16 brain: UCH-L1 and nestin (C); UCH-L1 and TuJ1 (D). UCH-L1 and nestin are co-expressed in the VZ at E14 and E16. Nestin is expressed only in radial glial fibers (arrowheads) of the CP but not in neurons. UCH-L1 expression level is high. A representative cell with a high level of UCH-LI expression is indicated by a white arrow and one with low expression is indicated by a yellow arrow (C). An early neuronal marker, TuJ1, was expressed in both migrating (arrowheads) and mature neurons (D). CP, cortical plate; IZ, intermediate zone; MZ, marginal zone; SVZ, subventricular zone; VZ, ventricular zone. Bars, 40 m.
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Ubiquitin C-terminal hydrolase L1 (UCH-L1) is a component of the ubiquitin system, which has a fundamental role in regulating various biological activities. However, the functional role of the ubiquitin system in neurogenesis is not known. Here we show that UCH-L1 regulates the morphology of neural progenitor cells (NPCs) and mediates neurogenesis....
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Despite recent efforts in discovering novel long non-coding RNAs (lncRNAs) and unveiling their functions in a wide range of biological processes their applications as biotechnological or therapeutic tools are still at their infancy. We have recently shown that AS Uchl1, a natural lncRNA antisense to the Parkinson’s disease-associated gene Ubiquitin...
Background
The proteins S100B, neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and neurofilament light (NF-L) have been serially sampled in serum of patients suffering from traumatic brain injury (TBI) in order to assess injury severity and tissue fate. We review the current l...
Citations
... It also preserves axonal conductance and improves motor behavior after stroke via decreasing polyubiquitinated protein accumulation [21]. Importantly, UCHL1 spatially mediates neurogenesis in the embryonic brain by regulating the morphology of neural progenitor cells (NPCs) [22]. However, the potential effects of UCHL1 on spinal cord NSCs remain unclear. ...
... Importantly, targeted upregulation of UCHL1 enhanced the activation of Nestin + NSCs response to injury in adult SCI animals. Moreover, discoveries [22] suggested that UCHL1 promote neuronal differentiation and neurogenesis of Nestin + progenitors in the embryonic brain. Interestingly, a few newborn neurons (BrdU/Tubulin β3 + and BrdU/NeuN + neurons) were detected in the injured spinal cord here after UCHL1 upregulation in Nestin + NSCs by AAV. ...
... Although certain differences between the fetal and adult NSCs, our data show that UCHL1 enhanced both of their activation in vitro and in vivo separately, supporting the pivotal role of UCHL1-related UPP in NSC activation. The potential mechanism underlying the promotive effects of UCHL1 on NSCs may largely attribute to its regulatory effects on ubiquitin-proteasome activity as previously described [12,22]. ...
Activation of endogenous neural stem cells (NSCs) is greatly significant for the adult neurogenesis; however, it is extremely limited in the spinal cord after injury. Recent evidence suggests that accumulation of protein aggregates impairs the ability of quiescent NSCs to activate. Ubiquitin c-terminal hydrolase l-1 (UCHL1), an important deubiquitinating enzyme, plays critical roles in protein aggregations clearance, but its effects on NSC activation remains unknown. Here, we show that UCHL1 promotes NSC activation by clearing protein aggregates through ubiquitin-proteasome approach. Upregulation of UCHL1 facilitated the proliferation of spinal cord NSCs after spinal cord injury (SCI). Based on protein microarray analysis of SCI cerebrospinal fluid, it is further revealed that C3 ⁺ neurotoxic reactive astrocytes negatively regulated UCHL1 and proteasome activity via C3/C3aR signaling, led to increased abundances of protein aggregations and decreased NSC proliferation. Furthermore, blockade of reactive astrocytes or C3/C3aR pathway enhanced NSC activation post-SCI by reserving UCHL1 and proteasome functions. Together, this study elucidated a mechanism regulating NSC activation in the adult spinal cord involving the UCHL1-proteasome approach, which may provide potential molecular targets and new insights for NSC fate regulation.
... However, high expression of UCHL1 was found in primary lung tumours (both small and non-small cell lung cancer) [6,7]. UCHL1 is also involved in cell apoptosis, neuronal differentiation, synaptic functions, and contextual memory [8,9]. Although higher epithelial expression of UCHL1 has been reported in smokers, the underlying molecular mechanism is not fully understood, and a role for UCHL1 in the pathogenesis of lung diseases remains to be determined. ...
Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) is highly expressed in smokers, but little is known about the molecular mechanism of UCHL1 in airway epithelium and its possible role in affecting extracellular matrix (ECM) remodelling in the underlying submucosa. Since cigarette smoking is a major cause of lung diseases, we studied its effect on UCHL1 expression and DNA methylation patterns in human bronchial epithelial cells, obtained after laser capture micro-dissection (LCM) or isolated from residual tracheal/main stem bronchial tissue. Targeted regulation of UCHL1 expression via CRISPR/dCas9 based-epigenetic editing was used to explore the function of UCHL1 in lung epithelium. Our results show that cigarette smoke extract (CSE) stimulated the expression of UCHL1 in vitro. The methylation status of the UCHL1 gene was negatively associated with UCHL1 transcription in LCM-obtained airway epithelium at specific sites. Treatment with a UCHL1 inhibitor showed that the TGF-β1-induced upregulation of the ECM gene COL1A1 can be prevented by the inhibition of UCHL1 activity in cell lines. Furthermore, upon downregulation of UCHL1 by epigenetic editing using CRISPR/dCas-EZH2, mRNA expression of COL1A1 and fibronectin was reduced. In conclusion, we confirmed higher UCHL1 expression in current smokers compared to non- and ex-smokers, and induced downregulation of UCHL1 by epigenetic editing. The subsequent repression of genes encoding ECM proteins suggest a role for UCHL1 as a therapeutic target in fibrosis-related disease.
... It also preserves axonal conductance and improves motor behavior after stroke via decreases polyubiquitinated protein accumulation 22 . Importantly, UCHL1 spatially mediates neurogenesis in the embryonic brain by regulating the morphology of neural progenitor cells (NPCs) 23 . However, the potential effects of UCHL1 on spinal cord NSCs remain unclear. ...
... Although certain differences between the fetal and adult NSCs, these data show that UCHL1 enhanced both of their activation in vitro and in vivo, which support the pivotal role of UCHL1-related UPP in NSCs fate mediation. The potential mechanism underlying the promotive effects of UCHL1 on NSCs may largely attribute to its regulatory effects on ubiquitin-proteasome activity as previously described 23,54 . ...
Activation of endogenous neural stem cells (NSCs) is greatly significant for the adult neurogenesis, which is extremely limited in the non-neurogenic spinal cord after injury. Recent evidence suggests that accumulation of protein aggregates impairs the ability of quiescent NSCs to activate. Ubiquitin c-terminal hydrolase l-1 (UCHL1), an important deubiquitinating enzyme in ubiquitin system, plays critical role in removing protein aggregations, but its effects on NSC activation remains unknown. Here, we show that UCHL1 enhances NSC activation by clearing protein aggregates through ubiquitin-proteasome approach. Upregulation of UCHL1 ameliorated the proliferation of spinal cord NSCs after spinal cord injury (SCI). Based on protein microarray analysis of SCI cerebrospinal fluid, it is further revealed that C3 ⁺ neurotoxic reactive astrocytes negatively regulated UCHL1 and proteasome activity via C3/C3aR signaling, led to increased abundances of protein aggregations and decreased capacity of NSCs to activate. Furthermore, blockade of reactive astrocytes or C3/C3aR pathway resulted in enhanced NSC activation post-SCI by reserving UCHL1 and proteasome functions. Together, this study elucidated a mechanism regulating NSC activation in the adult spinal cord involving the UCHL1-proteasome approach, which may provide potential molecular targets and new insights for NSC fate regulation.
... It also preserves axonal conductance and improves motor behavior after stroke via decreases polyubiquitinated protein accumulation 26 . In addition, research has reported that UCHL1 could spatially mediates neurogenesis in the embryonic brain by regulating the morphology of neural progenitor cells (NPCs) 27 . Moreover, UCHL1 has been shown to be signi cantly upregulated in the Nestin + active NSCs post-SCI 9 . ...
... In line with this study, a few newborn neurons (BrdU/Tubulin β3 + and BrdU/NeuN + neurons) were observed here after UCHL1 upregulation in Nestin + NSCs by AAV. The potential mechanism underlying the promotive role of UCHL1 on NSCs largely attributes to its regulatory effects on ubiquitin-proteasome activity as previously described 27,45 . In addition, UCHL1 has been shown to decrease neurite injury and improve sensorimotor recovery after cerebral ischemia 26 . ...
Activation of the endogenous neural stem cells (NSCs) is critically important for the adult neurogenesis. However, NSC activation is extremely limited in the non-neurogenic spinal cord after spinal cord injury (SCI). Recent evidence suggests that accumulation of protein aggregates impedes quiescent NSC activation. Here, we found that ubiquitin c-terminal hydrolase l-1 (UCHL1), an important deubiquitinating enzyme, functioned to facilitate NSC activation by clearing protein aggregations through ubiquitin-proteasome pathway. Based on protein microarray analysis of SCI cerebrospinal fluid, it is further revealed that C3 ⁺ neurotoxic reactive astrocytes negatively regulated UCHL1 and the subsequent protein aggregations clearance to restrict NSC activation via C3/C3aR signaling. Upregulation of UCHL1 and blockade of reactive astrocytes or C3/C3aR pathway efficiently enhanced Nestin ⁺ NSC activation after SCI. Together, this study elucidated a mechanism regulating NSC activation in the adult spinal cord involving the UCHL1-proteasome approach, providing a promising strategy and novel molecular targets for SCI repair.
... Although it remains unknown whether UCHL1 is involved in osteogenesis, it has been demonstrated to regulate cell differentiation under different pathophysiological conditions. UCHL1 enhanced neurogenesis during embryonic brain development (Sakurai et al. 2006), while it exhibited altered expression and inhibited myoblast cell differentiation in disease conditions (Gao et al. 2017). In view of these findings, we speculated a possible role of UCHL1 in the impaired osteogenesis of PDLSCs in periodontitis. ...
Periodontitis comprises a series of inflammatory responses resulting in alveolar bone loss. The suppression of osteogenesis of periodontal ligament stem cells (PDLSCs) by inflammation is responsible for impaired alveolar bone regeneration, which remains an ongoing challenge for periodontitis therapy. Ubiquitin C-terminal hydrolase L1 (UCHL1) belongs to the family of deubiquitinating enzymes, which was found to play roles in inflammation previously. In this study, the upregulation of UCHL1 was identified in inflamed PDLSCs isolated from periodontitis patients and in healthy PDLSCs treated with tumor necrosis factor–α or interleukin–1β, and the higher expression level of UCHL1 was accompanied with the impaired osteogenesis of PDLSCs. Then UCHL1 was inhibited in PDLSCs using the lentivirus or inhibitor, and the osteogenesis of PDLSCs suppressed by inflammation was rescued by UCHL1 inhibition. Mechanistically, the negative effect of UCHL1 on the osteogenesis of PDLSCs was attributable to its negative regulation of mitophagy-dependent bone morphogenetic protein 2/Smad signaling pathway in periodontitis-associated inflammation. Furthermore, a ligature-induced murine periodontitis model was established, and the specific inhibitor of UCHL1 was administrated to periodontitis mice. The histological results showed increased active osteoblasts on alveolar bone surface and enhanced alveolar bone regeneration when UCHL1 was inhibited in periodontitis mice. Besides, the therapeutic effects of UCHL1 inhibition on ameliorating periodontitis were verified, as indicated by less bone loss and reduced inflammation. Altogether, our study proved UCHL1 to be a key negative regulator of the osteogenesis of PDLSCs in periodontitis and suggested that UCHL1 inhibition holds promise for alveolar bone regeneration in periodontitis treatment.
... Anapc2 (100)(101)(102)(103)(104)(105)(106)(107)(108)(109)(110)(111)(112)(113)(114)(115) and Anapc11 (⁓ 49 TPM) were the major genes of the catalytic core. Transcripts of the other component (Anapc10) were near the detection level (2-3 TPM) (Fig. 6A). ...
... Isolated from brain extracts, UCH-L1 was originally described as a neuronal marker [113]. In a previous study on the brain, Uch-l1 mRNA was detected in early stages of embryonic development [114] and was found in progenitor cells and neurons [115]. UCH-L1 has been postulated to facilitate neurogenesis and determine the morphology of progenitor cells [115]. ...
... In a previous study on the brain, Uch-l1 mRNA was detected in early stages of embryonic development [114] and was found in progenitor cells and neurons [115]. UCH-L1 has been postulated to facilitate neurogenesis and determine the morphology of progenitor cells [115]. The precise roles UCH-L1 plays in neuronal physiology are, however, poorly understood, but UCH-L1 dysfunction has been associated with several age-related neurodegenerative processes, such as Alzheimer's and Parkinson's diseases [116]. ...
Ubiquitination involves three types of enzymes (E1, E2, and E3) that sequentially attach ubiquitin (Ub) to target proteins. This posttranslational modification controls key cellular processes, such as the degradation, endocytosis, subcellular localization and activity of proteins. Ubiquitination, which can be reversed by deubiquitinating enzymes (DUBs), plays important roles during brain development. Furthermore, deregulation of the Ub system is linked to the pathogenesis of various diseases, including neurodegenerative disorders. We used a publicly available RNA-seq database to perform an extensive genome-wide gene expression analysis of the core components of the ubiquitination machinery, covering Ub genes as well as E1, E2, E3 and DUB genes. The ubiquitination network was governed by only Uba1 and Ube2m , the predominant E1 and E2 genes, respectively; their expression was positively regulated during cortical formation. The principal genes encoding HECT (homologous to the E6-AP carboxyl terminus), RBR (RING-in-between-RING), and RING (really interesting new gene) E3 Ub ligases were also highly regulated. Pja1 , Dtx3 (RING ligases) and Stub1 (U-box RING) were the most highly expressed E3 Ub ligase genes and displayed distinct developmental expression patterns. Moreover, more than 80 DUB genes were expressed during corticogenesis, with two prominent genes, Uch-l1 and Usp22, showing highly upregulated expression. Several components of the Ub system overexpressed in cancers were also highly expressed in the cerebral cortex under conditions not related to tumour formation or progression. Altogether, this work provides an in-depth overview of transcriptomic changes during embryonic formation of the cerebral cortex. The data also offer new insight into the characterization of the Ub system and may contribute to a better understanding of its involvement in the pathogenesis of neurodevelopmental disorders.
... Similarly, Ubiquitin C-Terminal Hydrolase L1 (Uchl1) is a pan-neuronal marker that is also expressed by neural progenitor cells of the enteric nervous system and by neuroendocrine cells [63][64][65] . ...
BACKGROUND & AIMS
Efforts to characterize the signaling mechanisms that underlie gastroenteropancreatic neoplasms (GEP-NENs) are precluded by a lack of comprehensive model systems that recapitulate pathogenesis. Investigation into a potential cell-of-origin for gastrin-secreting NENs revealed a role for enteric glia in neuroendocrine cell specification. Here we investigated the hypothesis that loss of menin in glial cells stimulated neuroendocrine differentiation and tumorigenesis.
METHODS
Using Cre-lox technology, we generated a conditional glial fibrillary acidic protein-directed Men1 knockout ( GFAP ΔMen1 ) mouse model. Cre specificity was confirmed using a tdTomato reporter. GFAP ΔMen1 mice were evaluated for GEP-NEN development and neuroendocrine cell hyperplasia. siRNA-mediated Men1 silencing in a rat enteric glial cell line was performed in parallel.
RESULTS
GFAP ΔMen1 mice developed pancreatic NENs, in addition to pituitary prolactinomas that phenocopied the human MEN1 syndrome. GFAP ΔMen1 mice exhibited gastric neuroendocrine hyperplasia that coincided with a significant loss of GFAP expression. Mechanistically, Men1 deletion induced reprogramming from a mature glial phenotype toward a neuroendocrine lineage. Furthermore, blockade of Hedgehog signaling in enteric glia attenuated neuroendocrine hyperplasia by restricting the neuroendocrine cell fate.
CONCLUSIONS
GFAP-directed Men1 inactivation exploits glial cell plasticity in favor of neuroendocrine differentiation.
GRAPHICAL ABSTRACT
... Generally, kidney damage markers are albuminuria/proteinuria, serum creatinine and a reduction in estimated glomerular filtration rate (eGFR), which is also a critical marker of CKD in the kidney. In addition, novel biomarkers, such as α-klotho, Nephrin gene (NPHS1), Synaptopodin and so on, for estimating kidney function and renal inflammatory response have been reported in diabetic animal and human studies [1][2][3][4][5][6][7][8][9]. ...
... Many studies have strongly asserted that three biomarkers mentioned above (α-klotho, Nephrin, Synaptopodin) are also available to detect the risks for future cognitive impairment and neurodegenerative disorders early in diabetic animals with renal damage [2,[4][5][6][7][9][10][11][12]. Moreover, since the above three markers are found in BBB in the brain [8,[12][13][14][15][16], it is expected to be closely related to the study of dementia caused by kidney disease. ...
... Each podocyte's cell body has a number of primary processes that extend and further divide, giving rise to interdigitating secondary processes that completely cover the glomerular basement membrane. Due to these morphological characteristics, recent research has emphasized biochemical and functional similarities between podocytes and neuronal cells [7]. The Nephrin gene in the rodent model is known to be distributed in various regions within the central nervous system (CNS), and a neurological phenotype was recently reported for Nephrin-KO mice after selective rescue of Nephrin in the kidney [6]. ...
It is recently known that the kidney and brain have a very rich distribution of blood vessels, and the histological structures of micro-vessels are very similar. Therefore, a number of studies have reported that renal diseases like chronic kidney disease (CKD) caused by various causes have a very close relationship with the occurrence of neurodegenerative diseases. On the other hand, since diabetic nephropathy, which is caused by chronic inflammation, such as diabetes, often shows very different prognoses even in patients at the same clinical stage, the judgment of their disease prognosis will have a critical meaning in clinical practice. Recently, many studies of cerebro-renal interaction have been reported using experimental animals. The discovery of common biomarkers found in both organs can predict the prognosis of renal disease and the possibility of neurodegenerative disease progression. More associations can be found with novel common biomarkers found in the brain and kidneys that seem entirely unrelated. In that case, it will ultimately be a research field that can expand predictive models of patients' complex diseases through these biomarkers in clinical practice. It is presented biomarkers such as α-klotho, Nephrin, and Synaptopodin. These markers are observed in both the brain and kidney, and it has been reported that both organs show a very significant change in function according to their expression. Even though the brain and kidneys perform very independent functions, it is thought that it has a crucial diagnostic significance that the genes commonly expressed in both organs are functionally effective. With the discovery of novel biomarkers that share cerebro-renal interactions at the early stage of diabetic nephropathy, physicians can predict post-clinical symptoms and prevent severe neurodegenerative and cerebrovascular diseases. Therefore, further study for the diseases of these two organs in laboratory animals means that the field of research on this relationship can be expanded in the future. In the future, more attention and research will be needed on the possibility of prediction for the prevention of neurological diseases caused by CKD in disease animal models.
... It is found to be upregulated during acute SCI. The phosphorylation of Ubiquitin Carboxyl-terminal hydrolase L1 (UCH-L1) and conjugated ubiquitin is increased, which in turn, regulates neurogenesis and promotes neuronal progenitor cells (Sakurai et al., 2006). On the other hand, Ubiquitin-specific protease 4 (USP4) belongs to the deubiquitinase family which inhibits the NF-κB pathway. ...
Degradomics is a subdscipline of proteomics, it refers to the study of proteases, the enzymes responsible for the hydrolysis
of peptide bonds, and the study of breakdown products (BDPs) ensuing from the targeted substrates. Among the techniques that were used to decipher the degradomic profiling in neurotrauma, mass spectrometry has proved to be the most efficacious in conveying the precise measurements of BDPs, proteases, and substrates. Several disease states produce an array of BDPs resulting from an uncontrolled protease-substrate repertoire, that could be further used in the diagnosis, assessment, treatment, and follow-up. Spinal Cord Injury (SCI) can be divided into a primary injury, where the shear forces of the direct trauma disrupt the axonal relays, causing disability, and a secondary injury, where neurotoxicity plays a key role. The latter can exacerbate the former injury and slows the recovery, which will lead to a downward spiral of cellular and molecular activation, alterations of proteolytic enzymes, and cytotoxic neurotransmitters, and impaired blood–CNS barrier.
... Recent studies demonstrated that DCX may be responsible for cancer metastasis and uncontrolled migration of cancer cells [30,33]. UCHL-1 is a neural marker that regulates neural progenitor cell differentiation, thereby enhancing neurogenesis in the embryonic brain [34]. No neural cells were detected. ...
... It is also expressed in a variety of cancers where it promotes tumor cell mobility and metastasis [33]. The second neural marker, UCHL-1 (alias PGP9.5), is a unique brainspecific deubiquitinating enzyme upregulated also in neuroblastoma, acute lymphoblastic leukemia, non-small cell lung cancer, and renal cell carcinoma [34,41]. Of clinical interest, its inhibition might reduce cell invasiveness [38]. ...
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressive hematologic malignancy originating from plasmacytoid dendritic cells (pDCs). The microRNA expression profile of BPDCN was compared to that of normal pDCs and the impact of miRNA dysregulation on the BPDCN transcriptional program was assessed. MiRNA and gene expression profiling data were integrated to obtain the BPDCN miRNA-regulatory network. The biological process mainly dysregulated by this network was predicted to be neurogenesis, a phenomenon raising growing interest in solid tumors. Neurogenesis was explored in BPDCN by querying different molecular sources (RNA sequencing, Chromatin immunoprecipitation-sequencing, and immunohistochemistry). It was shown that BPDCN cells upregulated neural mitogen genes possibly critical for tumor dissemination, expressed neuronal progenitor markers involved in cell migration, exchanged acetylcholine neurotransmitter, and overexpressed multiple neural receptors that may stimulate tumor proliferation, migration and cross-talk with the nervous system. Most neural genes upregulated in BPDCN are currently investigated as therapeutic targets.
