Journal of Neurochemistry最新文献

{"title":"Exosome-Derived CDC42 From Hypoxia-Pretreated Neural Stem Cells Inhibits ACSL4-Related Ferroptosis to Alleviate Vascular Injury in Parkinson's Disease Mice Models","authors":"You Li,&nbsp;Junwen Jiang,&nbsp;Jiameng Li,&nbsp;Siliang Liu,&nbsp;Chuang Wang,&nbsp;Zhengtao Yu,&nbsp;Ying Xia","doi":"10.1111/jnc.70027","DOIUrl":"https://doi.org/10.1111/jnc.70027","url":null,"abstract":"<div>\u0000 \u0000 <p>Parkinson's disease (PD) is a neurodegenerative disorder that gets exacerbated by vascular injury. Neural stem cell-derived exosomes (NSC-Exos) display effective neuroprotective properties in PD models. Cell division control protein 42 (CDC42) is connected to angiogenesis, but its effects in PD remain undefined. This research aims to reveal the role of CDC42 in PD. First, we applied 1-methyl-4-phenylpyridinium (MPP⁺) to induce the human cerebral microvascular endothelial cells (HCMECs) model and evaluated cell viability and ferroptosis. Then, we characterized NSC-Exos. Next, to appraise the effect of hypoxia-pretreated NSC-Exos (H-NSC-Exos) on the MPP⁺-induced cells model, we examined angiogenesis and ferroptosis in HCMECs. Moreover, we constructed the PD mice model using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and tested the behavioral experiments and vascular injury of mice. Furthermore, we examined cellular ferroptosis and angiogenesis after knockdown of CDC42. Additionally, we investigated the interaction of CDC42 with Acyl-CoA synthetase long-chain family member 4 (ACSL4) and detected cellular ferroptosis and angiogenesis after overexpression of ACSL4. We found that H-NSC-Exos reversed the MPP⁺-induced decrease in HCMECs viability and migration, lowered lipid-reactive oxygen species (lipid-ROS) levels, suppressed ferroptosis, and facilitated angiogenesis. Moreover, H-NSC-Exos attenuated MPTP-induced PD development, vascular injury, and ferroptosis in mice. H-NSC-Exos with the knockdown of CDC42 reduced cell viability and angiogenesis and raised ferroptosis and lipid-ROS levels, which were reversed by ferrostatin-1 and liproxstatin-1. CDC42 interacted with ACSL4. Furthermore, overexpression of ACSL4 aggravated the above effects of H-NSC-Exos in which CDC42 was knocked down. Our study reveals that H-NSC-Exos-derived CDC42 inhibited ACSL4-related ferroptosis to alleviate vascular injury in PD mice models. CDC42 may serve as a potent therapeutic target for PD treatment.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143535831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preface to the Special Issue “Matrix Metalloproteinases in Health and Disease”","authors":"Mathew Amontree,&nbsp;Katherine Conant","doi":"10.1111/jnc.70032","DOIUrl":"https://doi.org/10.1111/jnc.70032","url":null,"abstract":"<p>This preface introduces a collection of new work focused on matrix metalloproteinases (MMPs) and select MMP substrates in the nervous system. Discovered over 60 years ago during the study of collagen degradation during tadpole tail metamorphosis by Gross and Lapiere, MMPs are now known to play critical roles in adaptive and non-adaptive physiological processes in varied species. Though early studies focused predominantly on their role in inflammation, wound healing, and angiogenesis, work during the last 20 years has expanded to include an abundance of studies related to MMPs and their substrates in brain disease and plasticity. Particularly novel and intriguing studies are numerous and include those related to the role of MMPs in mood and memory, as well as studies of select MMP substrates in critical period closure. The manuscripts herein include a review of MMP-9, an MMP that is released from resident cells of the brain, including neurons and microglia, as well as a comprehensive review of perineuronal nets (PNNs), which are composed of MMP substrates including brevican. Additional manuscripts focus on fragile X messenger ribonucleoprotein 1 product (FMRP) in the translational regulation of aggrecan, an important PNN component, as well as manuscripts showing PNN chondroitin sulfate-glycosaminoglycan compositional changes in a mouse model of tauopathy, a novel localization of PNN-like structures in the enteric nervous system, a mechanism by which MMP-2 could contribute to the disruption of the blood-brain barrier, and differential effects of a sirtuin agonist on glial and neuronal MMP release.</p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70032","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143530285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CPNE7 Regulates Amyloidogenesis Through CAP1-Dependent ADAM10 Translation","authors":"Jie Yang,&nbsp;Ya-Lan Pu,&nbsp;Qiu-Lin Pan,&nbsp;Lu Wang,&nbsp;Chen-Lu Li,&nbsp;Xiao-Yong Xie,&nbsp;Xue Chen,&nbsp;Xiao-Yun Li,&nbsp;Ding-Qun Bai,&nbsp;Bing-Lin Zhu,&nbsp;Guo-Jun Chen","doi":"10.1111/jnc.70026","DOIUrl":"https://doi.org/10.1111/jnc.70026","url":null,"abstract":"<div>\u0000 \u0000 <p>The accumulation of amyloid plaques is a pathological hallmark of Alzheimer's disease (AD), in which ADAM10, the α-secretase that catalyzes APP and facilitates the non-amyloidogenesis pathway, plays an important role. We have previously reported that the expression of copine-7 (Cpne7) in the hippocampus of APP/PS1 mice is significantly upregulated by nicotine, whereas the potential role of CPNE7 in AD remains largely unknown. Here, we report that CPNE7 protein levels are significantly decreased in APP/PS1 mice and HEK293 cells stably expressing full-length APP. CPNE7 is shown to reduce Aβ levels by favoring ADAM10 activity, and the elevated ADAM10 protein by CPNE7 involves a translational mechanism. Further transcriptome profiling reveals that CPNE7 differentially regulates genes associated with neuronal function. Among these, cyclase-associated actin cytoskeleton regulatory protein 1 (CAP1) is identified as a target gene of CPNE7, which controls ADAM10 translation through binding to the 5′ untranslated region (5′UTR). Collectively, the CPNE7-CAP1 axis could be critical in the amyloidogenic pathway by regulating ADAM10 translation, in which the RNA binding activity of CAP1 is highlighted.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143530287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Limitations and Applications of Rodent Models in Tauopathy and Synucleinopathy Research","authors":"Emma Szegvari,&nbsp;Sara A. M. Holec,&nbsp;Amanda L. Woerman","doi":"10.1111/jnc.70021","DOIUrl":"https://doi.org/10.1111/jnc.70021","url":null,"abstract":"<p>Rodent models that accurately recapitulate key aspects of human disease have long been fundamental to the successful development of clinical interventions. This is greatly underscored in the neurodegenerative disease field, where preclinical testing of anti-prion therapeutics against rodent-adapted prions resulted in the development of small molecules effective against rodent-adapted prions but not against human prions. These findings provided critical lessons for ongoing efforts to develop treatments for patients with neurodegenerative diseases caused by misfolding and accumulation of the proteins tau and α-synuclein, or tauopathies and synucleinopathies, respectively. To avoid the potential pitfalls previously identified in the prion field, this review focuses on rodent models currently available to study tau and α-synuclein disease pathogenesis, emphasizing the strengths and limitations of each with the particular goal of better supporting preclinical research.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70021","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143530286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Role of the Urea Cycle in the Alzheimer's Disease Brain","authors":"Najlaa A. Al-Thani,&nbsp;Gavin S. Stewart,&nbsp;Derek A. Costello","doi":"10.1111/jnc.70033","DOIUrl":"https://doi.org/10.1111/jnc.70033","url":null,"abstract":"<p>Alzheimer's Disease (AD) is a neurodegenerative disorder classified as the leading form of dementia in the elderly. Classical hallmarks of AD pathology believed to cause AD include Amyloid-beta (Aβ) plaques as well as neurofibrillary tau tangles (NTT). However, research into these classical hallmarks has failed to account for a causative link or therapeutic success. More recently, metabolic hallmarks of AD pathology have become a popular avenue of research. Elevated urea and ammonia detected in cases of AD point towards a dysfunctional urea cycle involved in AD. This review covers the expansive body of literature surrounding the work of researchers deciphering the role of the urea cycle in AD pathology through the study of urea cycle enzymes, metabolites, and transporters in the AD brain. Urea cycle enzymes of interest in AD pathology include OTC, NOS isoforms, ARG1, ARG2, MAOB, and ODC, which all present as promising therapeutic targets. Urea metabolites indicated in AD pathology have varying concentrations across the regions of the brain and the different cell types (neurons, microglia, astrocytes). Finally, the role of UT-B as a clearance modulator presents this protein as a key target for research in the role of the urea cycle in the AD brain. In the future, these key enzymes, pathways, and proteins relating to the urea cycle in AD should be further investigated to better understand the cell-specific urea cycle profiles in the AD brain and uncover their therapeutic potential.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70033","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serotonergic Psychedelics Rapidly Modulate Evoked Glutamate Release in Cultured Cortical Neurons","authors":"Aneta Petrušková,&nbsp;Debarpan Guhathakurta,&nbsp;Enes Yağız Akdaş,&nbsp;Bartomeu Perelló-Amorós,&nbsp;Renato Frischknecht,&nbsp;Eva-Maria Weiss,&nbsp;Tomáš Páleníček,&nbsp;Anna Fejtová","doi":"10.1111/jnc.70020","DOIUrl":"https://doi.org/10.1111/jnc.70020","url":null,"abstract":"<p>The serotonergic psychedelics psilocybin, LSD and DMT hold great promise for the development of new treatments for psychiatric conditions such as major depressive disorder, addiction and end-of-life anxiety. Previous studies in both animals and humans have confirmed the effects of these drugs on neuronal activity and plasticity. However, the understanding of the mechanisms of action of these substances is limited. Here we show rapid effects of psychedelics on presynaptic properties, using live cell imaging at the level of single synapses in primary rat cortical neurons. Using the genetically encoded reporter of synaptic vesicle fusion synaptopHluorin, we detected a reduced fraction of synaptic vesicles that fused in response to mild or strong electrical stimulation 3–30 min after application of serotonergic psychedelics. These effects were transient and no longer present 24 h after treatment. While DMT only reduced the total recycling pool, LSD and psilocin also reduced the size of the readily releasable vesicle pool. Imaging with the sensors for glutamate, iGluSnFR, and presynaptic calcium, synGCaMP6, showed that while psilocin and DMT increased evoked glutamate release, LSD and psilocin reduced evoked presynaptic calcium levels. Interestingly, psilocin also affected short-term plasticity leading to a depression of responses to paired stimuli. The rapid and drug-specific modulation of glutamatergic neurotransmission described in this study may contribute to distinct anxiolytic and antidepressant properties of serotonergic psychedelics.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70020","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microglia-Mediated Synaptic Dysfunction Contributes to Chemotherapy-Related Cognitive Impairment","authors":"Jingxiong Wang,&nbsp;Hua Zhang,&nbsp;Marc Augenreich,&nbsp;Luis Martinez-Lemus A,&nbsp;Zhenguo Liu,&nbsp;Xunlei Kang,&nbsp;Bo Lu,&nbsp;Hui-Ming Chang,&nbsp;Edward T. H. Yeh,&nbsp;Juan Cata,&nbsp;Srikant Rangaraju,&nbsp;Heike Wulff,&nbsp;De-Pei Li","doi":"10.1111/jnc.70024","DOIUrl":"https://doi.org/10.1111/jnc.70024","url":null,"abstract":"<div>\u0000 \u0000 <p>Chemotherapy-related cognitive impairment (CRCI) significantly impacts cancer survivors. Due to unclear mechanisms, effective treatments for cognitive deficits are lacking. Here, we examined if microglia-mediated deficits in synaptic plasticity drive CRCI. Adult male mice were treated with the chemotherapeutic drugs 5-fluorouracil and leucovorin (5-Fu/LV, intraperitoneal injection, I.P.) on Days 1, 8, and 15 at a dosage of 50 mg/kg for 5-Fu and 90 mg/kg for LV for 3 weeks. Cognitive function was assessed using a novel object recognition (NOR) test 4 weeks after completion of 5-Fu/LV treatment. Compared with vehicle treatment, 5-Fu/LV treatment reduced the preference for exploring novel objects in the NOR test. Treatment with 5-Fu/LV increased the numbers of Iba1-positive microglial and CD68-positive/Iba1-positive microglia with shortened process lengths and diminished endpoints but decreased the number of phagocytotic (≤ 1 FITC-labeled beads) Iba1-positive microglia. Furthermore, 5-Fu/LV treatment reduced the long-term potentiation (LTP) recorded in the hippocampal CA1 region in response to a theta burst stimulation of the CA3-CA1 pathway and decreased the evoked N-methyl-D-aspartic acid receptor (NMDAR)-excitatory postsynaptic currents (NMDAR-EPSCs) in CA1 neurons. Cotreatment with the microglial inhibitor minocycline (33 mg/kg, daily for 3 weeks) restored cognitive deficits and microglial ramification, decreased the number of CD68-positive microglia, and reversed the reductions in LTP and the amplitude of NMDAR-EPSCs in 5-Fu/LV-treated mice. Our data suggest that microglial dysfunction and related synaptic dysfunction contribute to 5-Fu/LV-induced cognitive impairment.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 \u0000 \u0000 </p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143513607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Calcium-Dependent Signaling in Astrocytes: Downstream Mechanisms and Implications for Cognition","authors":"Alexandra Veiga,&nbsp;Daniela Sofia Abreu,&nbsp;José Duarte Dias,&nbsp;Patrícia Azenha,&nbsp;Sara Barsanti,&nbsp;João Filipe Oliveira","doi":"10.1111/jnc.70019","DOIUrl":"https://doi.org/10.1111/jnc.70019","url":null,"abstract":"<p>Astrocytes are glial cells recognized for their diverse roles in regulating brain circuit structure and function. They can sense and adapt to changes in the microenvironment due to their unique structural and biochemical properties. A key aspect of astrocytic function involves calcium (Ca²⁺)-dependent signaling, which serves as a fundamental mechanism for their interactions with neurons and other cells in the brain. However, while significant progress has been made in understanding the spatio-temporal properties of astrocytic Ca²⁺ signals, the downstream molecular pathways and exact mechanisms through which astrocytes decode these signals to regulate homeostatic and physiological processes remain poorly understood. To address this topic, we review here the available literature on the sources of intracellular Ca²⁺, as well as its downstream mechanisms and signaling pathways. We review the well-studied Ca²⁺-dependent exocytosis but draw attention to additional intracellular Ca²⁺-dependent mechanisms that are less understood and are, most likely, highly influential for many other cellular functions. Finally, we review how intracellular Ca²⁺ is thought to underlie neuron–astrocyte signaling in brain regions involved in cognitive processing.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70019","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143475759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Upregulation of FMRP Is Involved in Neuropathic Pain by Regulating GluN2B Activation in Rat Spinal Cord","authors":"Lei Chen,&nbsp;Xuejiao Guo,&nbsp;Long Zhang,&nbsp;Yunze Li,&nbsp;Li Zhou,&nbsp;Jinsong Zhao,&nbsp;Yujia Luo,&nbsp;Yanling Hu,&nbsp;Xiaowei Chen,&nbsp;Xianhui Kang,&nbsp;Xiangming Fang,&nbsp;Zhiying Feng","doi":"10.1111/jnc.70022","DOIUrl":"https://doi.org/10.1111/jnc.70022","url":null,"abstract":"<div>\u0000 \u0000 <p>Fragile X mental retardation protein (FMRP) has been proposed to play a potential role in the pathogenesis of autonomy and nociceptive paresthesia. However, the involvement of spinal FMRP in neuropathic pain remains unexplored. Using a rat model of neuropathic pain induced by chronic constriction injury (CCI), our investigation demonstrated an upregulation of FMRP at 3, 7, and 14 days post-CCI operation in the spinal dorsal horn (SDH). Immunofluorescence staining revealed predominant FMRP expression in spinal neurons, which colocalized with Glutamate Ionotropic Receptor NMDA Type Subunit 2B (GluN2B). The Co-immunoprecipitation results suggested an interaction between spinal FMRP and GluN2B. Genetic knockout of the Fmr1 gene or transient interference with the FMRP protein alleviated CCI-induced pain hypersensitivity and suppressed the increase in spinal GluN2B expression. Conversely, intrathecal administration of the GluN2B-specific inhibitor Ifenprodil significantly suppressed the CCI-induced increase in spinal FMRP expression. In conclusion, our findings highlight the pivotal role of spinal FMRP in developing neuropathic pain and modulating GluN2B levels within the SDH. Furthermore, our results suggest a reciprocal regulatory relationship, indicating that GluN2B may also influence FMRP expression. This study provides insights into the molecular mechanisms underlying neuropathic pain, suggesting the potential for therapeutic intervention targeting the FMRP-GluN2B axis in pain management.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143475760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Deubiquitinase USP2 Modulates Photic Entrainment of the Circadian Clock at the Level of the Suprachiasmatic Nucleus","authors":"Shashank B. Srikanta,&nbsp;Thomas W. Brown,&nbsp;Antoine Malescot,&nbsp;Marie-Ève Cloutier,&nbsp;Lei Zhu,&nbsp;Christine Coutanson,&nbsp;Maryam Malki,&nbsp;Kai-Florian Storch,&nbsp;Ravi Rungta,&nbsp;Michel Cayouette,&nbsp;Ouria Dkhissi-Benyahya,&nbsp;Nicolas Cermakian","doi":"10.1111/jnc.70018","DOIUrl":"https://doi.org/10.1111/jnc.70018","url":null,"abstract":"<p>Ubiquitin-specific peptidase 2 (USP2) is a deubiquitinase (DUB) with a diversity of functions in physiology. One of these functions is the regulation of circadian rhythms, which are physiological rhythms with a period of ~24 h. Previous studies have indicated a role for USP2 in photic entrainment, the process by which circadian clocks synchronize to environmental light cues. Here, we investigated the implication of USP2 in this process, using <i>Usp2</i> knockout (KO) mice. Using different light treatments and running wheel recordings, we established that USP2 controls entrainment of the clock to light cues at dusk. Further, we showed that <i>Usp2</i> is expressed throughout the suprachiasmatic nucleus (SCN), the site of the central clock, and in the retina. This raised the question of where USP2 acts on circadian photoreception. We found that it is not within the retina, as retinas of <i>Usp2</i> KO mice have an intact structure and unaltered photoreception through intrinsically photosensitive retinal ganglion cells. Moreover, KO of <i>Usp2</i> within the retina does not alter clock entrainment to light. In contract, KO of <i>Usp2</i> in the SCN causes a light entrainment phenotype similar to full-body KO mice, showing that the action of USP2 in modulating photic entrainment predominantly takes place in the SCN. Finally, within the SCN, we found that induction of clock gene <i>Per1</i> and activation of MAPK/ERK pathway in response to light were blunted in <i>Usp2</i> KO mice. Altogether, we established a key role for USP2 in regulating photic entrainment by modulating light-responsive pathways within the SCN.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70018","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143438770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}