Neurobiology of Disease最新文献

{"title":"Lessons from the Tim Greenamyre model.","authors":"Laurie H Sanders, Nancy Blechman, Sarah Berman, Erwan Bezard, Fabio Blandini, Jason Cannon, Mark Cookson, Briana De Miranda, Roberto Di Maio, Robert Drolet, Jim Greene, Jessica Kappel, Mark Kaufmann, Matthew Keeney, Arthur S Levine, Abby Olsen, Teddy Pettus, Sean Pintchovski, Ian Reynolds, Emily Rocha, William Shrader, Valerie Suski, Malú Gámez Tansey, Anne Young, Pier Mastroberardino","doi":"10.1016/j.nbd.2025.106995","DOIUrl":"10.1016/j.nbd.2025.106995","url":null,"abstract":"","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"106995"},"PeriodicalIF":5.1,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275406","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":"Immune control of the basal ganglia network: Interleukin-17 as a key modulator of striatal synaptic plasticity","authors":"Andrea Mancini ,&nbsp;Laura Bellingacci ,&nbsp;Jacopo Canonichesi ,&nbsp;Miriam Sciaccaluga ,&nbsp;Alfredo Megaro ,&nbsp;Elisa Zianni ,&nbsp;Maria De Carluccio ,&nbsp;Marilena Pariano ,&nbsp;Edoardo Emiliano ,&nbsp;Alessandro Tozzi ,&nbsp;Cinzia Costa ,&nbsp;Teresa Zelante ,&nbsp;Luigina Romani ,&nbsp;Maria Teresa Viscomi ,&nbsp;Fabrizio Gardoni ,&nbsp;Paolo Calabresi ,&nbsp;Lucilla Parnetti ,&nbsp;Massimiliano Di Filippo","doi":"10.1016/j.nbd.2025.106994","DOIUrl":"10.1016/j.nbd.2025.106994","url":null,"abstract":"<div><div>The basal ganglia (BG) network exerts a key role in the integration of cortical inputs and is fundamental to motor learning, behavior, emotional responses, and cognitive functions. Little is known about how immune cells and soluble immune mediators influence BG activity. Interleukin-17A (IL-17A) is in the spotlight for its emerging role as a neuromodulator of cortical synaptic transmission and plasticity in physiological and pathological conditions. However, its role at the level of subcortical structures such as the BG circuit is still unclear. In this study, we demonstrate that striatal medium spiny neurons (MSNs) highly express IL-17RA and that the IL-17 axis contributes to the physiological expression of synaptic plasticity in these cells. Indeed, long-term potentiation (LTP) induction was significantly reduced in mice lacking IL-17A or IL-17RA. This effect might rely on an altered glutamatergic transmission, as synaptic expression of NMDAR subunit GluN2B is reduced in mice lacking IL-17A. At the same time, exposure to high concentrations of IL-17A was found to impair LTP induction through modulation of NMDAR currents. These results suggest a dual effect of this cytokine on striatal synaptic plasticity, showing the IL-17 axis as a key neuromodulator of the BG circuit, with potential implications in the pathogenesis of neuroinflammatory and neuropsychiatric disorders.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 106994"},"PeriodicalIF":5.1,"publicationDate":"2025-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144266809","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":"ANKK1, ANKRD50, GRK5, PACSIN1 and VPS8 are novel candidate genes associated with late onset Parkinson's disease: Definition of a novel predictive protocol based on polygenic model of inheritance","authors":"Federica Carrillo ,&nbsp;Nicole Piera Palomba ,&nbsp;Sara Pietracupa ,&nbsp;Laura Ianiro ,&nbsp;Giorgio Fortunato ,&nbsp;Margherita Degasperi ,&nbsp;Tiziana Giloni ,&nbsp;Maria Ilenia De Bartolo ,&nbsp;Luigi Pavone ,&nbsp;Teresa Nutile ,&nbsp;Nicola Modugno ,&nbsp;Danilo Licastro ,&nbsp;Teresa Esposito","doi":"10.1016/j.nbd.2025.106996","DOIUrl":"10.1016/j.nbd.2025.106996","url":null,"abstract":"<div><div>Parkinson's disease (PD) represents one of the most frequent neurodegenerative disorders for which genetic diagnosis is still challenging due to the high genetic heterogeneity associated with the disease and to the difficulty in interpreting test results. We have recently reported the identification of rare new gene variants in PD patients that support polygenic contribution to the disease. Here we report the identification of novel candidate PD genes and an exploratory protocol for predictive analysis of PD risk.</div><div>The study includes the whole exome data of 22 PD families, 300 unrelated familiar PD, 504 unrelated sporadic PD and 664 healthy subjects. Family-based approach identified rare and disrupting variants in 44 candidate PD genes co-inherited by affected relatives. The analysis of the entire cohort discovered a significant excess of rare and deleterious variants in PD patients compared to controls in 7 genes out of the 44 identified in the families. Five of these, known as <em>ANKK1, ANKRD50, GRK5, PACSIN1</em> and <em>VPS8,</em> were novel candidate PD genes, expressed in human dopaminergic neurons, and involved in signal transduction pathways and in endocytic recycling. In these genes, we identified both rare probably damaging variants, altering protein structure and dynamics, as well as frequent variants associated with PD risk. Moreover, we demonstrated that the co-inheritance of multiple rare variants (≥ 2) in a panel of 37 PD genes selected in this study, may predict disease risk in about 26 % of patients, both familial and sporadic cases, with high specificity (&gt; 92 %; <em>p</em> ≤0.00001). Furthermore, patients carrying multiple rare variants showed higher risk of manifesting dyskinesia induced by levodopa treatment (<em>p</em> = 0.004), severe cognitive impairment (<em>p</em> = 0.009) and an earlier age at onset of the disease (<em>p</em> = 0.01). Despite the still exploratory nature of the study, these data provide novel insights into the genetic of PD and may be relevant for its prediction, diagnosis and treatment.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 106996"},"PeriodicalIF":5.1,"publicationDate":"2025-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144255162","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":"Inhibitory circuit dysfunction as a potential contributor to cortical reorganization in Glioblastoma progression","authors":"Cristina Spalletti ,&nbsp;Marta Scalera ,&nbsp;Elisabetta Mori ,&nbsp;Sabrin Haddad ,&nbsp;Marco Mainardi ,&nbsp;Daniele Cangi ,&nbsp;Vinoshene Pillai ,&nbsp;Elena Parmigiani ,&nbsp;Silvia Landi ,&nbsp;Matteo Caleo ,&nbsp;Eleonora Vannini","doi":"10.1016/j.nbd.2025.106997","DOIUrl":"10.1016/j.nbd.2025.106997","url":null,"abstract":"<div><div>Glioblastoma (GBM) is a highly aggressive brain tumor that infiltrates surrounding brain tissue, profoundly affecting adjacent cortical areas. This study investigates how GBM reshapes the peritumoral cortex by examining plasticity changes in two GBM mouse models. Using optogenetic stimulation, we observed altered motor mapping and reduced cortical specificity in GBM mice compared to controls. Morphologically, GBM mice showed a reduction in dendritic spines, perineuronal nets, and inhibitory markers. Functionally, inhibitory circuits were markedly impaired, characterized by an increased frequency of spontaneous inhibitory currents and a decrease in their amplitude. Our findings highlight the critical role of inhibitory circuit disruption in driving cortical reorganization and loss of motor map specificity. The reduction of parvalbumin and somatostatin interneurons, degradation of perineuronal nets, and imbalance in the excitation/inhibition ratio contribute to maladaptive plasticity, increasing the risk of hyperexcitability and seizures. These insights offer a basis for developing therapeutic strategies aimed at restoring inhibitory function, mitigating GBM-induced cortical changes, and potentially improving patient outcomes.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 106997"},"PeriodicalIF":5.1,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144258525","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":"Neuromodulation of voltage-gated sodium channels by Gβ1γ2 subunits: Implications for GNB1-linked encephalopathy","authors":"Nicholas Denomme ,&nbsp;Samantha L. Hodges ,&nbsp;Luis Lopez-Santiago ,&nbsp;Yukun Yuan ,&nbsp;Julie M. Ziobro ,&nbsp;Joe Minton ,&nbsp;Chunling Chen ,&nbsp;Yan Chen ,&nbsp;Jacob M. Hull ,&nbsp;James Offord ,&nbsp;Alan V. Smrcka ,&nbsp;Lori L. Isom","doi":"10.1016/j.nbd.2025.106990","DOIUrl":"10.1016/j.nbd.2025.106990","url":null,"abstract":"<div><div>Guanine nucleotide-binding protein Gβγ subunits are ubiquitous signaling molecules that interact with numerous effector proteins in neurons, including voltage-gated sodium, calcium, and potassium channels. We show that Gβγ subunits associate with voltage-gated sodium channels (Na_vs) in mouse brain, and co-expression of a prominent Gβγ complex, Gβ1γ2, leads to functional inhibition of brain Na_v α subunit subtypes Na_v1.1 and Na_v1.6 in heterologous cells. Gβ1γ2 co-expression shows subtype-selective effects on Na_v1.1 and Na_v1.6 in the presence of Na_vβ1 subunit co-expression, and in response to prepulse voltage changes. De novo variants in <em>GNB1</em>, encoding the Gβ1 subunit, are linked to <em>GNB1</em> encephalopathy (<em>GNB1</em>-E). Using cortical slice electrophysiology, we show that the <em>Gnb1</em>^K78R/+ mouse model of <em>GNB1</em>-E has reduced spontaneous GABAergic, but not glutamatergic, transmission and decreased sodium current density in dissociated parvalbumin-expressing GABAergic interneurons. This work advances our understanding of the epileptic mechanisms present in <em>GNB1</em>-E, including a previously unrecognized role for Na_vs.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 106990"},"PeriodicalIF":5.1,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248805","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":"TDP-43 mutants with different aggregation properties exhibit distinct toxicity, axonal transport, and secretion for disease progression in a mouse ALS/FTLD model","authors":"Hideki Mori ,&nbsp;Tokiharu Sato ,&nbsp;Shintaro Tsuboguchi ,&nbsp;Masahiko Takahashi ,&nbsp;Yuka Nakamura ,&nbsp;Kana Hoshina ,&nbsp;Taisuke Kato ,&nbsp;Masahiro Fujii ,&nbsp;Osamu Onodera ,&nbsp;Masaki Ueno","doi":"10.1016/j.nbd.2025.106988","DOIUrl":"10.1016/j.nbd.2025.106988","url":null,"abstract":"<div><div>TDP-43 accumulates and forms inclusions in neurons in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) and is assumed to cause neurodegenerative processes. The morphologies and cellular and areal distributions of accumulated TDP-43 inclusions are pathologically diverse among ALS/FTLD patients; however, whether and how different types of TDP-43 affect the process and severity of disease progression are not fully understood. Here, we compared the pathological events evoked by TDP-43 mutations, which have different aggregation properties, in cultured neurons and the cerebral cortex in mice. We selected TDP-43^C173/175S and TDP-43^G298S as aggregation-prone and nonprone mutants, respectively. Cytoplasmically expressed TDP-43^C173/175S induced insoluble inclusions more robustly than TDP-43^G298S did. In contrast, TDP-43^G298S induced cell death more severely than TDP-43^C173/175S. TDP-43^G298S was further found to be efficiently transported in axons and led to axon degeneration, while this effect was not obvious in TDP-43^C173/175S. Instead, TDP-43^C173/175S was frequently trapped in the axon initial segments. Finally, TDP-43^G298S was secreted in exosomes and transferred to oligodendrocyte-lineage cells in vitro more efficiently than TDP-43^C173/175S to induce cell death. The transfer further evoked cytokine responses in microglial cells. These data revealed that different aggregation properties of TDP-43 cause distinct pathological events. These findings may explain the differences in the neurodegenerative progression and distribution observed among patients with ALS and FTLD.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"212 ","pages":"Article 106988"},"PeriodicalIF":5.1,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144243500","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":"Sigma-1R–Pom121 axis preserves nuclear transport and integrity in poly-PR-induced C9orf72 ALS","authors":"Chun-Yu Lin ,&nbsp;Hsuan-Cheng Wu ,&nbsp;Ru-Huei Fu ,&nbsp;Eddie Feng-Ju Weng ,&nbsp;Wen-Chi Hsieh ,&nbsp;Tsung-Ping Su ,&nbsp;Hsiang-En Wu ,&nbsp;Shao-Ming Wang","doi":"10.1016/j.nbd.2025.106992","DOIUrl":"10.1016/j.nbd.2025.106992","url":null,"abstract":"<div><div>Nucleocytoplasmic transport disruption contributes to the pathogenesis of <em>C9orf72</em>-associated amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Among the dipeptide repeat proteins translated from G4C2-repeat RNA, poly-PR is particularly toxic, compromising nuclear envelope integrity and transport. Here, we revealed that poly-PR reduced expression of the nucleoporin Pom121 in NSC-34 cells and in an AAV-mediated poly-PR₄₂ mouse model, resulting in cytoplasmic mislocalization of the neuroprotective transcription factor ATF3 and nuclear envelope damage. Pom121 overexpression restored nuclear ATF3 localization and alleviated poly-PR-induced toxicity. We further identified Sigma-1 receptor (Sigma-1R) as a stabilizer of Pom121 that preserved nuclear integrity and ATF3 function under oxidative stress. Overexpression of Sigma-1R, Pom121, or ATF3 rescued poly-PR-induced cytotoxicity. Our findings defined a protective Sigma-1R/Pom121/ATF3 axis and suggested this pathway as a therapeutic target in <em>C9orf72</em>-linked ALS.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"212 ","pages":"Article 106992"},"PeriodicalIF":5.1,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144243518","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":"Calcium-iron crosstalk in epileptogenesis: Unraveling mechanisms and therapeutic opportunities","authors":"Xuan Li ,&nbsp;Ao-Long Tao ,&nbsp;Nayiyuan Wu ,&nbsp;Xiu Zhang ,&nbsp;Fen Xiao ,&nbsp;Jing Wang ,&nbsp;Zhi-Bin Wang","doi":"10.1016/j.nbd.2025.106989","DOIUrl":"10.1016/j.nbd.2025.106989","url":null,"abstract":"<div><div>Epilepsy, a chronic neurological disorder affecting millions globally, remains poorly understood in its etiology and therapeutic management. Emerging evidence highlights the intricate interplay between calcium (Ca²⁺) and iron (Fe²⁺/Fe³⁺) ions in modulating neuronal excitability, oxidative stress, and synaptic plasticity—key processes implicated in epileptogenesis. This review synthesizes current knowledge on the dual roles of Ca²⁺ and Fe²⁺/Fe³⁺ in epilepsy, emphasizing their bidirectional regulatory mechanisms and pathological synergism. Calcium dysregulation, mediated through voltage-gated channels (e.g., Cav1.2, Cav3.2), store-operated calcium entry (SOCE), and mitochondrial calcium uniporters (MCU), exacerbates neuronal hyperexcitability and seizure propagation. Concurrently, iron overload drives ferroptosis via lipid peroxidation and glutathione depletion, while iron deficiency impairs neurodevelopmental processes. Crucially, Ca²⁺-Fe²⁺ crosstalk intersects at multiple nodes: TRP channels (e.g., TRPC6, TRPML1) facilitate dual ion transport; mitochondrial dysfunction links Ca²⁺ overload with Fe²⁺-dependent ROS generation; and inflammatory cascades disrupt both ion homeostasis. Clinically, antiepileptic drugs targeting Ca²⁺ channels (e.g., ethosuximide, zonisamide) and emerging ferroptosis inhibitors (e.g., deferoxamine, RTA 408) underscore the therapeutic potential of modulating these pathways. However, drug resistance and incomplete seizure control necessitate novel strategies leveraging ion interaction networks. We propose that combinatorial approaches targeting Ca²⁺-Fe²⁺ signaling hubs—such as MCU-TRPML1 axes or redox-sensitive RyR channels—may offer synergistic benefits. Future research must prioritize cross-model validation, advanced neuroimaging biomarkers, and multidisciplinary frameworks to translate mechanistic insights into precision therapies. This comprehensive analysis positions Ca²⁺-Fe²⁺ crosstalk as a pivotal frontier in epilepsy research, bridging molecular pathophysiology with innovative treatment paradigms.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"212 ","pages":"Article 106989"},"PeriodicalIF":5.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144243517","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":"Comprehensive characterization and validation of the Prp-hPFN1G118V mouse model: Guidelines for preclinical therapeutic testing for ALS","authors":"Kaly A. Mueller ,&nbsp;Emma G. Suneby ,&nbsp;Matthew H. Ferola ,&nbsp;Andy J. Moreno ,&nbsp;Joshua D. Kidd ,&nbsp;Kenneth Thompson ,&nbsp;Fernando G. Vieira ,&nbsp;Gregorio Valdez ,&nbsp;Theo Hatzipetros","doi":"10.1016/j.nbd.2025.106975","DOIUrl":"10.1016/j.nbd.2025.106975","url":null,"abstract":"<div><div>The hPFN1^G118V mouse model, overexpressing mutant human profilin1 linked to a rare form of ALS, was comprehensively characterized to assess its suitability for preclinical drug testing. Using a large cohort of nearly 250 transgenic and wild-type mice in a longitudinal study, we combined behavioral, electrophysiological, and neuropathological assessments to define the chronology of pathological events and assess inherent subject variability. The early stage of the disease in this model was characterized by elevated plasma neurofilament light chain levels, an effect that persisted and progressed throughout the course of the disease, followed by spinal cord neuroinflammation, suggesting that axonal pathology is the initiating event. The middle stage of the disease involved progressive neuromuscular decline, including reductions in compound muscle action potential (CMAP) and grip strength, accompanied by neuromuscular junction degeneration. The end-stage of the disease was characterized by the onset of visible changes such as weight loss, gait abnormalities and hindlimb paresis that quickly progressed to paralysis. At end-stage we also observed spinal motor neuron loss and TDP-43 pathology. The average humane endpoint was 213 days for females and 237 days for males. Our findings demonstrate that hPFN1^G118V mice recapitulate key ALS features with moderate disease progression and a reproducible disease course, making them a valuable model for therapeutic testing. Recommendations are provided to optimize study design for preclinical testing, emphasizing survival duration as the primary endpoint, with CMAP and plasma NFL as key secondary readouts.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"212 ","pages":"Article 106975"},"PeriodicalIF":5.1,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144222884","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":"SARM1 activation induces reversible mitochondrial dysfunction and can be prevented in human neurons by antisense oligonucleotides","authors":"Andrea Loreto ,&nbsp;Kaitlyn M.L. Cramb ,&nbsp;Lucy A. McDermott ,&nbsp;Christina Antoniou ,&nbsp;Ilenia Cirilli ,&nbsp;Maria Claudia Caiazza ,&nbsp;Elisa Merlini ,&nbsp;Peter Arthur-Farraj ,&nbsp;W. Daniel du Preez ,&nbsp;Elliot D. Mock ,&nbsp;Hien T. Zhao ,&nbsp;David L. Bennett ,&nbsp;Giuseppe Orsomando ,&nbsp;Michael P. Coleman ,&nbsp;Richard Wade-Martins","doi":"10.1016/j.nbd.2025.106986","DOIUrl":"10.1016/j.nbd.2025.106986","url":null,"abstract":"<div><div>SARM1 is a key regulator of a conserved program of axon degeneration increasingly linked to human neurodegenerative diseases. Pathological SARM1 activation causes rapid NAD consumption, disrupting cellular homeostasis and leading to axon degeneration. In this study, we develop antisense oligonucleotides (ASOs) targeting human SARM1, demonstrating robust neuroprotection against morphological, metabolic, and mitochondrial impairment in human iPSC-derived dopamine neurons induced by the lethal neurotoxin vacor, a potent SARM1 activator. Furthermore, our findings reveal that axon fragmentation can be prevented, and mitochondrial dysfunction reversed using the NAD precursor nicotinamide, a form of vitamin B₃, even after SARM1 activation has occurred, when neurons are already unhealthy. This research identifies ASOs as a promising therapeutic strategy to block SARM1, and provides an extensive characterisation and further mechanistic insights that demonstrate the reversibility of SARM1 toxicity in human neurons. It also identifies the SARM1 activator vacor as a specific and reversible neuroablative agent in human neurons.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 106986"},"PeriodicalIF":5.1,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234627","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}