Loss of UCHL1 rescues the defects related to Parkinson’s disease by suppressing glycolysis

Ham, Su Jin; Lee, Daewon; Xu, Wen; Cho, Eunjoo; Choi, Sekyu; Min, Soohong; Park, Sunghyouk; Chung, Jongkyeong

doi:10.1126/sciadv.abg4574

Cited by 38 publications

(27 citation statements)

References 68 publications

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“…Growing evidence has indicated that UCHL1 could function via inhibiting mitophagy (Cerqueira et al 2020; Ham et al 2021), which is a positive regulator of osteogenesis (Pei et al 2018; Lee et al 2021). Hence, we explored whether mitophagy was involved in the UCHL1-regulated osteogenesis.…”

Section: Resultsmentioning

confidence: 99%

UCHL1 Impairs Periodontal Ligament Stem Cell Osteogenesis in Periodontitis

Lin

et al. 2022

J Dent Res

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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.

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Section: Resultsmentioning

confidence: 99%

UCHL1 Impairs Periodontal Ligament Stem Cell Osteogenesis in Periodontitis

Lin

et al. 2022

J Dent Res

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“… 145 Moreover, loss of ubiquitin carboxyl-terminal hydrolase L1 in knockout models was recently observed to rescue PD-related defects through suppression of glycolysis. 146 In addition to biochemically linking one of the leading TBI biomarkers to PD, this finding demonstrates that a multiomic understanding of the pathophysiology of TBI is important for investigating how TBI relates to other neurological diseases.…”

Section: Proteomic Biomarkersmentioning

confidence: 91%

Progress Toward a Multiomic Understanding of Traumatic Brain Injury: A Review

et al. 2022

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Traumatic brain injury (TBI) is not a single disease state but describes an array of conditions associated with insult or injury to the brain. While some individuals with TBI recover within a few days or months, others present with persistent symptoms that can cause disability, neuropsychological trauma, and even death. Understanding, diagnosing, and treating TBI is extremely complex for many reasons, including the variable biomechanics of head impact, differences in severity and location of injury, and individual patient characteristics. Because of these confounding factors, the development of reliable diagnostics and targeted treatments for brain injury remains elusive. We argue that the development of effective diagnostic and therapeutic strategies for TBI requires a deep understanding of human neurophysiology at the molecular level and that the framework of multiomics may provide some effective solutions for the diagnosis and treatment of this challenging condition. To this end, we present here a comprehensive review of TBI biomarker candidates from across the multiomic disciplines and compare them with known signatures associated with other neuropsychological conditions, including Alzheimer’s disease and Parkinson’s disease. We believe that this integrated view will facilitate a deeper understanding of the pathophysiology of TBI and its potential links to other neurological diseases.

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“…Another observation cohort study on HIE (hypoxic-ischemic encephalopathy) patients (neonate patients = 16, controls = 11) also found that UCHL1 was elevated in HIE neonates and associated with cortical injury (36). As a protein biomarkers for central nervous system damage, UCHL1 has been detected in diverse brain injuries including ischemic/hemorrhagic stroke (37,38), TBI (39, 40), Parkinson's disease (41), cardiac arrest (42), and seizures (43).…”

Section: Potential Use Of Uchl1 As Peripheral Blood Biomarker For Neurological Complications In Covid-19 Patientsmentioning

confidence: 99%

Biomarkers and Immune Repertoire Metrics Identified by Peripheral Blood Transcriptomic Sequencing Reveal the Pathogenesis of COVID-19

Liu

et al. 2021

Front. Immunol.

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The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a global crisis; however, our current understanding of the host immune response to SARS-CoV-2 infection remains limited. Herein, we performed RNA sequencing using peripheral blood from acute and convalescent patients and interrogated the dynamic changes of adaptive immune response to SARS-CoV-2 infection over time. Our results revealed numerous alterations in these cohorts in terms of gene expression profiles and the features of immune repertoire. Moreover, a machine learning method was developed and resulted in the identification of five independent biomarkers and a collection of biomarkers that could accurately differentiate and predict the development of COVID-19. Interestingly, the increased expression of one of these biomarkers, UCHL1, a molecule related to nervous system damage, was associated with the clustering of severe symptoms. Importantly, analyses on immune repertoire metrics revealed the distinct kinetics of T-cell and B-cell responses to SARS-CoV-2 infection, with B-cell response plateaued in the acute phase and declined thereafter, whereas T-cell response can be maintained for up to 6 months post-infection onset and T-cell clonality was positively correlated with the serum level of anti-SARS-CoV-2 IgG. Together, the significantly altered genes or biomarkers, as well as the abnormally high levels of B-cell response in acute infection, may contribute to the pathogenesis of COVID-19 through mediating inflammation and immune responses, whereas prolonged T-cell response in the convalescents might help these patients in preventing reinfection. Thus, our findings could provide insight into the underlying molecular mechanism of host immune response to COVID-19 and facilitate the development of novel therapeutic strategies and effective vaccines.

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Loss of UCHL1 rescues the defects related to Parkinson’s disease by suppressing glycolysis

Cited by 38 publications

References 68 publications

UCHL1 Impairs Periodontal Ligament Stem Cell Osteogenesis in Periodontitis

UCHL1 Impairs Periodontal Ligament Stem Cell Osteogenesis in Periodontitis

Progress Toward a Multiomic Understanding of Traumatic Brain Injury: A Review

Biomarkers and Immune Repertoire Metrics Identified by Peripheral Blood Transcriptomic Sequencing Reveal the Pathogenesis of COVID-19

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