Yue-ting Zhong , Chao Pi , Ying Zuo , Yan Wei , Wen Li , Yong-qiang Jiang , Lei Tao , Wen-wu Zheng , Jun Jiang , Yan Yang , Shi-feng Chu , Bin-yan Liu , Ke-zhi Liu , Yu-meng Wei , Ling Zhao
{"title":"The P2X7 receptor in depression: Novel insights and therapeutic implications","authors":"Yue-ting Zhong , Chao Pi , Ying Zuo , Yan Wei , Wen Li , Yong-qiang Jiang , Lei Tao , Wen-wu Zheng , Jun Jiang , Yan Yang , Shi-feng Chu , Bin-yan Liu , Ke-zhi Liu , Yu-meng Wei , Ling Zhao","doi":"10.1016/j.nbd.2025.107011","DOIUrl":"10.1016/j.nbd.2025.107011","url":null,"abstract":"<div><div>Major depressive disorder (MDD) is a heterogeneous mental disorder involving multiple pathogenic mechanisms. Current first-line antidepressant medications suffer from slow onset of action, limited effectiveness, and high side effects, necessitating the search for new therapeutic targets. Targeting cytokines or receptors is increasingly recognized in innovative depression treatment protocols. The P2X7 receptor (P2X7R) plays a key role in central nervous system signaling and is considered a potential therapeutic target for depression. Recent studies have focused on the fact that P2X7R modulates inflammatory and immune responses, which may contribute to the development of depression. However, the full extent of P2X7R's involvement in depression remains unclear. This review provides a comprehensive overview of the discovery, structure, and properties of P2X7R. We delve into the role of P2X7R in the pathogenesis of depression, focusing on neuroinflammation, oxidative stress, mitochondrial dysfunction, and reduced synaptic plasticity. Additionally, we discuss the clinical applications of P2X7R antagonists. By highlighting the significant role and therapeutic potential of the P2X7 receptor as a pharmacological target for depression, this review aims to provide new research perspectives and theoretical basis for the development of antidepressant drugs.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 107011"},"PeriodicalIF":5.1,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144518130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Helen Zhao , Dan Zhou , Yolanda Feng , Gabriel G. Haddad
{"title":"Klinefelter syndrome: A neurodevelopmental disease of the synapse","authors":"Helen Zhao , Dan Zhou , Yolanda Feng , Gabriel G. Haddad","doi":"10.1016/j.nbd.2025.107010","DOIUrl":"10.1016/j.nbd.2025.107010","url":null,"abstract":"<div><div><em>Klinefelter syndrome (KS; 47,XXY)</em> is the most common sex chromosome disorder, affecting approximately 1 in every 500 to 650 newborn males. Children with KS display a spectrum of phenotypic manifestations, including abnormal neurocognitive phenotypes. However, due to the limited research focusing on the central nervous system, our understanding of the neurobiology of KS at the cellular and molecular levels remains largely unclear. In this study, we utilized cortical organoids derived from pluripotent stem cells and transcriptomic analysis to explore the mechanisms underlying early brain developmental defects in KS patients. We demonstrate that KS organoids display altered neurogenesis, gliogenesis, and glutamate signaling pathways. We believe these early alterations contribute to the abnormal brain development and later cognitive phenotypes in KS patients.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 107010"},"PeriodicalIF":5.1,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144512183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kevin S. Chen , Mohamed H. Noureldein , Diana M. Rigan , John M. Hayes , Kyle J. Loi , Junguk Hur , Masha G. Savelieff , Eva L. Feldman
{"title":"Interneuron transcriptomics reveals pathologic markers of Alzheimer's disease progression","authors":"Kevin S. Chen , Mohamed H. Noureldein , Diana M. Rigan , John M. Hayes , Kyle J. Loi , Junguk Hur , Masha G. Savelieff , Eva L. Feldman","doi":"10.1016/j.nbd.2025.107012","DOIUrl":"10.1016/j.nbd.2025.107012","url":null,"abstract":"<div><div>Alzheimer's disease (AD) exhibits imbalance between neuronal excitation and inhibition, likely secondary to interneuron dysfunction. To reveal underlying mediators, we spatially profiled the transcriptome of neuronal subtypes in 5XFAD versus control mice at early- and late-stage disease. Pooled analysis of neuron types showed expected pathways at early-stage (RNA and protein processing pathways) versus late-stage (neurodegenerative pathways) disease. Early-stage interneurons exhibited alterations in AD-related RNA and protein pathways along with canonical neurodegenerative pathways. Early-stage excitatory neurons, however, showed changes in axon guidance and synapse pathways, without representation of neurodegenerative pathways. Classical neurodegenerative pathways were represented only in late-stage excitatory neurons. Late-stage interneurons instead featured neuronal and synapse pathways along with cellular, cancer, and infection pathways. Our results suggest earlier neurodegenerative pathway involvement in interneurons, represented in excitatory neurons only at later stages, possibly indicating earlier inhibitory neuron involvement. These transcriptomic profiles offer insight into potential AD pathophysiology and therapeutic targets.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 107012"},"PeriodicalIF":5.1,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144512182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Laura Dubach , Alberto Averna , Laura Alva , Ines Debove , Elena Bernasconi , Mario Sousa , Katrin Petermann , Martin Lenard Lachenmayer , Paul Krack , Andreas Nowacki , Claudio Pollo , Vladimir Krejci , Gerd Tinkhauser
{"title":"Unconsciousness reshapes the oscillatory topography of the subthalamic nucleus: A comparative study","authors":"Laura Dubach , Alberto Averna , Laura Alva , Ines Debove , Elena Bernasconi , Mario Sousa , Katrin Petermann , Martin Lenard Lachenmayer , Paul Krack , Andreas Nowacki , Claudio Pollo , Vladimir Krejci , Gerd Tinkhauser","doi":"10.1016/j.nbd.2025.107009","DOIUrl":"10.1016/j.nbd.2025.107009","url":null,"abstract":"<div><h3>Background</h3><div>Many centers perform Deep Brain Stimulation (DBS) surgery under general anesthesia (GA), known as asleep DBS. Local field potential (LFP) of the Subthalamic Nucleus (STN) recorded in awake Parkinson's disease (PD) patients revealed important insights into disease mechanism and DBS optimization-strategies. In contrast, the spectral characteristics of oscillations recorded in the GA-induced unconscious state remain only partially understood.</div></div><div><h3>Objectives</h3><div>To contrast the spectral and topographical characteristics of STN-LFPs recorded in both awake and asleep states and assess the clinical DBS response prediction based on neurophysiological hotspot positions.</div></div><div><h3>Methods</h3><div>STN-LFPs were recorded intraoperatively from 69 PD patients (128 hemispheres) awake and 26 patients (51 hemispheres) under propofol-anesthesia using multi-contact DBS electrodes. Spectral power (4 to 400 Hz), topographical hotspot distributions and their clinical predictive values were compared. The relationship between LFPs and frontal-EEG, anesthetic depth and dopamine withdrawal were also evaluated.</div></div><div><h3>Results</h3><div>Asleep LFPs showed increased alpha (8-12 Hz), low-beta (13-20 Hz), and fast-gamma (110-140 Hz) activity, and decreased theta (4-7 Hz), high-beta (21–30 Hz), and low-gamma (35-45 Hz) power, while high-gamma (60-90 Hz), slow-HFO (205-295 Hz) and fast-HFO (305-495 Hz) activity remained unchanged compared to the awake state. Under asleep DBS the spectral topographical map shifted medially, posteriorly and inferiorly, hereby losing its clinical predictive value. STN-LFPs echo propofol-induced changes in frontal-EEG, while time of dopamine withdrawal did not impact asleep-LFP.</div></div><div><h3>Conclusions</h3><div>Unconsciousness reshapes the spectral and spatial topography of the STN in PD patients, hereby losing its predictive values for motor DBS-response. Dynamical changes of spectral features in space may inform future sleep-tailored DBS.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 107009"},"PeriodicalIF":5.1,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144369093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yan Zhi , Kaidong Chen , Yiping You , Yi Ji , Weiguo Cheng , Wei Ji , Guofeng Shi , Xiangming Fang , Feng Wang , Kefei Chen , Li Zhang
{"title":"Hypo-connected pattern in Parkinson's disease with pure apathy: A dynamic functional connectivity perspective","authors":"Yan Zhi , Kaidong Chen , Yiping You , Yi Ji , Weiguo Cheng , Wei Ji , Guofeng Shi , Xiangming Fang , Feng Wang , Kefei Chen , Li Zhang","doi":"10.1016/j.nbd.2025.107008","DOIUrl":"10.1016/j.nbd.2025.107008","url":null,"abstract":"<div><h3>Background</h3><div>Apathy, a decline in goal-directed motivated behavior, is a common non-motor symptom in Parkinson's disease (PD). The dynamic information interaction between multiple brain functional networks, crucial for goal-directed behavior, remains unknown in patients with PD and pure apathy (PD-PA). This study thus used the dynamic functional network connectivity (dFNC) analysis to explore the dynamic brain networks changes of apathy in PD.</div></div><div><h3>Methods</h3><div>Thirty patients with PD-PA, 37 patients with PD but not pure apathy (PD-NPA), and 37 healthy controls (HCs) were studied using dFNC analysis to explore dynamic functional connectivity (FC) patterns of brain networks in PD-PA.</div></div><div><h3>Results</h3><div>Seven brain networks were finally identified and configured into four states. Patients with PD-PA showed longer mean dwell time in State 1 when compared to patients with PD-NPA. Furthermore, the mean dwell time of State 1 positively correlated with apathy severity in patients with PD-PA. Generally, State 1 is hypo-connected than other states. In State 1, intra-network FC within the default mode network (DMN) in patients with PD-PA was decreased compared to patients with PD-NPA. Specifically, the FC of the left precuneus and the left medial superior frontal gyrus (SFGmed) within the DMN was decreased.</div></div><div><h3>Conclusions</h3><div>Apathy in PD may be related with prolonged low connectivity in brain networks, particularly the disconnection between the precuneus and SFGmed within the DMN, highlighting impaired information transmission within and between networks as a key mechanism of apathy in PD.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 107008"},"PeriodicalIF":5.1,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Targeted neuromodulation of spinal interneurons enhances breathing in chronic spinal cord injury","authors":"Allison Brezinski , Nicholas Popp , Katherine Konkel , Shekar Kurpad , Kajana Satkunendrarajah","doi":"10.1016/j.nbd.2025.107007","DOIUrl":"10.1016/j.nbd.2025.107007","url":null,"abstract":"<div><div>Respiratory dysfunction is a debilitating consequence of cervical spinal cord injury (cSCI) with few available treatment options. Restoring function in the chronic phase is challenging due to the limited regenerative capacity of the adult central nervous system. This study investigates the targeted neuromodulation of cervical excitatory interneurons (eINs) to improve functional respiratory recovery in chronic cSCI. Cervical eINs, crucial for acute injury recovery, showed no reduction in numbers at 8- and 12-weeks post injury, highlighting their potential as neuromodulatory targets in the chronic phase. Targeted chemogenetic activation of these cervical eINs significantly improved breathing at 6- and 12-weeks post-cSCI. Repeated stimulation induced dendritic plasticity in respiratory spinal neurons without altering soma size. Notably, stimulation-mediated recovery at 12 weeks was comparable to that observed at 6 weeks underscoring the sustained efficacy of this approach. These findings highlight the potential of targeted neuromodulation of spinal interneurons to improve breathing in the chronic phase of SCI.</div></div><div><h3>Teaser</h3><div>Targeted stimulation of spinal neurons improves breathing long after cervical spinal cord injury, offering new hope for treatments.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 107007"},"PeriodicalIF":5.1,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144329815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chuan Hong , Xiaopeng Liu , Zhou Zhou , Yuan Xing , Zixuan Cao , Yan-Zhong Chang , Guofen Gao
{"title":"Role of Tropomodulins in brain physiology and pathology","authors":"Chuan Hong , Xiaopeng Liu , Zhou Zhou , Yuan Xing , Zixuan Cao , Yan-Zhong Chang , Guofen Gao","doi":"10.1016/j.nbd.2025.107006","DOIUrl":"10.1016/j.nbd.2025.107006","url":null,"abstract":"<div><div>Actin dynamics are crucial for the morphogenesis and function of neurons in the brain. Tropomodulins (Tmods) belong to a family of actin-binding proteins that cap the pointed-end of actin filaments. There are four Tmod isoforms, and three of which, Tmod1, Tmod2 and Tmod3, are expressed in the brain, with Tmod2 exhibiting neuronal specific expression. By regulating actin filament dynamics, Tmods participate in neurite outgrowth, dendritic spine formation, and synaptic morphology, thereby contributing to structural and functional neural plasticity. Dysregulation of Tmods has been demonstrated in several neurodegenerative and neuropsychiatric diseases, such as Alzheimer's disease, epilepsy, Down syndrome, and addictive behaviors. Currently, compared to cancer and cardiovascular diseases, the roles and mechanisms of altered Tmod expression in neurological diseases remain poorly understood. In this article, we provided an overview on the physiological roles and crucial functions of Tmods in the brain, summarized the recent advances in alterations of Tmods in neurodegenerative and neuropsychiatric diseases, and discussed their implications and potential contributions to disease pathology and treatment. This review may expedite future studies to delineate the roles and molecular mechanisms of Tmods in brain physiology and pathology, ultimately promoting the development of novel diagnostic and therapeutic strategies for related neurological diseases.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 107006"},"PeriodicalIF":5.1,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144297830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Carlos M. Díaz-Domínguez , Hasier Eraña , Francesca Peccati , Enric Vidal , Jorge M. Charco , Cristina Sampedro-Torres-Quevedo , Miguel A. Pérez-Castro , Nuria L. Lorenzo , Samanta Giler , Glenn C. Telling , Mariví Geijo , Jesús R. Requena , Gonzalo Jiménez-Osés , Joaquín Castilla
{"title":"Effect of primary structural variation on cervid prion protein in flexibility, stability, and spontaneous misfolding propensity","authors":"Carlos M. Díaz-Domínguez , Hasier Eraña , Francesca Peccati , Enric Vidal , Jorge M. Charco , Cristina Sampedro-Torres-Quevedo , Miguel A. Pérez-Castro , Nuria L. Lorenzo , Samanta Giler , Glenn C. Telling , Mariví Geijo , Jesús R. Requena , Gonzalo Jiménez-Osés , Joaquín Castilla","doi":"10.1016/j.nbd.2025.107005","DOIUrl":"10.1016/j.nbd.2025.107005","url":null,"abstract":"<div><div>Protein misfolding is central to numerous neurodegenerative disorders, collectively known as proteinopathies, which include Alzheimer's disease, Parkinson's disease, and prion diseases, among others. In many cases, specific polymorphisms of the proteins associated with these diseases influence their misfolding. However, the precise ways in which these polymorphisms affect protein integrity and how they contribute to misfolding propensity remain unclear. In the case of prion diseases, they are caused by prions or PrP<sup>Sc</sup>, the misfolded isoforms of the cellular prion protein (PrP<sup>C</sup>). Chronic Wasting Disease (CWD) is a prion disease that affects cervids and can exhibit lymphotropic properties, making it the most widespread proteinopathy. For that reason, cervid PrPs and their polymorphisms have been extensively studied. To better understand the role of these polymorphisms, we analyzed 45 cervid PrP variants to assess their effects on flexibility, stability, and spontaneous misfolding propensity.</div><div>The cervid variants were expressed as recombinant PrP in <em>E. coli</em> and were analyzed for thermal stability using circular dichroism. Additionally, the rec-PrPs served as substrates for Protein Misfolding Shaking Amplification (PMSA), enabling assessment of each variant's spontaneous misfolding propensity. This process led to the formation of <em>bona fide</em> prions, as confirmed by inoculation of one of the resulting conformers into transgenic mice expressing bank vole PrP. In parallel, molecular dynamics simulations were conducted to analyze the structural flexibility of the variants. While differences in protein flexibility were observed, no correlation was detected among flexibility, thermal stability, and the observed variable spontaneous misfolding propensity, suggesting that these properties are independent parameters.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 107005"},"PeriodicalIF":5.1,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Minghui Hu , Cui Lv , Jianping Zhu , Hao Zhang , Xinyu Wang , Luyan You , Jinlu Xie , Wei Liu , Xiaocen Wei , Kai Chen , Zifa Li , Sheng Wei , Xiwen Geng
{"title":"PD-1 deficiency disrupts in vivo neural activity in mouse Hippocampus and cortex","authors":"Minghui Hu , Cui Lv , Jianping Zhu , Hao Zhang , Xinyu Wang , Luyan You , Jinlu Xie , Wei Liu , Xiaocen Wei , Kai Chen , Zifa Li , Sheng Wei , Xiwen Geng","doi":"10.1016/j.nbd.2025.107002","DOIUrl":"10.1016/j.nbd.2025.107002","url":null,"abstract":"<div><div>Programmed cell death 1 (PD-1), encoded by the <em>Pdcd1</em> gene, was identified as a target in cancer immunotherapy but may result in the overactivation of T cell function and emotional changes such as anxiety. The dynamic changes in neuronal activity related to the anxious status caused by <em>Pdcd1</em><sup><em>−/−</em></sup> remain unclear. In this study, we addressed these physiological issues by simultaneously recording neuronal activity (spikes) and local field potentials (LFPs) in the medial prefrontal cortex (mPFC) and hippocampal CA3 region using <em>in vivo</em> multi-channel electrodes. Our results demonstrate that PD-1 deficiency induces anxiety-like behaviours and extensive neuronal firing disorders in the mPFC and CA3 regions of mice. The key finding was that in pyramidal neuron and interneurons in the CA3 region, the <em>in vivo</em> firing and spike-LFP encoding was disordered in the opposite direction by <em>Pdcd1</em><sup><em>−/−</em></sup>. These changes leaded to abnormal oscillations in mPFC and CA3 and disturbed mPFC neuronal firing. Targeting the activation of excitatory neurons in CA3 regions could rescue anxiety-like behaviours in <em>Pdcd1</em><sup><em>‐/</em></sup>‐ mice. This study provides physiological insights into the dynamic cooperation mechanisms between the mPFC and CA3 circuits in anxiety-like behaviours caused by <em>Pdcd1</em><sup><em>−/−</em></sup> and other mental disorders associated with autoimmune problems.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 107002"},"PeriodicalIF":5.1,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144294143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Francesco Formaggio , Asia Pizzi , Cecilia Delprete , Davide Pasqualini , Isabella Mataloni , Roberto Rimondini , Ludovica Campolongo , Vincenzo Donadio , Anna Maria Ghelli , Rocco Liguori , Marco Caprini
{"title":"Impaired plasma membrane calcium ATPase activity and mitochondrial dysfunction contribute to calcium dysregulation in Fabry disease-related painful neuropathy","authors":"Francesco Formaggio , Asia Pizzi , Cecilia Delprete , Davide Pasqualini , Isabella Mataloni , Roberto Rimondini , Ludovica Campolongo , Vincenzo Donadio , Anna Maria Ghelli , Rocco Liguori , Marco Caprini","doi":"10.1016/j.nbd.2025.107000","DOIUrl":"10.1016/j.nbd.2025.107000","url":null,"abstract":"<div><div>Neuropathic pain is a hallmark symptom in Fabry disease (FD), a hereditary X-linked lysosomal storage disorder caused by a reduced activity of α-galactosidase A (α-Gal A). The α-Gal A deficiency results in the progressive accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) in the body fluids and lysosomes of various cell types, including sensory ganglia. The FD neuropathy affects the small thinly myelinated Aδ fibers and unmyelinated C fibers leading to the loss of intra-epidermal neuronal terminations, along with altered thermal and mechanical perception. Lipid accumulation, such as Gb3 and lyso-Gb3, is implicated in various cellular dysfunctions, including the alteration of ionic currents. It has been shown that administration of Gb3 to human umbilical vein endothelial cells leads to the downregulation of the calcium (Ca<sup>2+</sup>)-activated K<sup>+</sup> channel K<sub>Ca</sub>3.1, whereas lyso-Gb3 evokes cytosolic Ca<sup>2+</sup> transients and an enhancement of voltage-activated Ca<sup>2+</sup> currents in murine dorsal root ganglia. Therefore, we examined the mechanism underlying Ca<sup>2+</sup> regulation in primary afferent neurons from the α-Gal A (−/0) mouse model. The obtained results suggest that other transport proteins participate in Ca<sup>2+</sup> homeostasis in FD and their dysfunction may be directly involved in nociception. In this context, plasma-membrane Ca<sup>2+</sup> ATPases exhibited reduced activity in FD, leading to an increased resting [Ca<sup>2+</sup>]<sub>i</sub> in sensory neurons. The reduced activity was associated with a decrease of cytosolic pH which weakened the PMCA-dependent calcium extrusion. We finally evaluated the contribution of mitochondria to the Ca<sup>2+</sup> signalling and we observed impairment of the mitochondrial buffer capacity, as well as dysfunctional mitochondria and enhanced autophagy/mitophagy. These findings provide a basis for future insights into the alterations of calcium signalling underlying the onset of neuropathic symptoms in FD.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 107000"},"PeriodicalIF":5.1,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144294142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}