Brain最新文献

{"title":"The role of dystrophin isoforms and interactors in the brain.","authors":"Konstantina Tetorou, Artadokht Aghaeipour, Simran Singh, Jennifer E Morgan, Francesco Muntoni","doi":"10.1093/brain/awae384","DOIUrl":"10.1093/brain/awae384","url":null,"abstract":"<p><p>Dystrophin is a protein crucial for maintaining the structural integrity of skeletal muscle. So far, attention has been focused on the role of dystrophin in muscle, in view of the devastating progression of weakness and early death that characterizes Duchenne muscular dystrophy. However, in the last few years, the role of shorter dystrophin isoforms, including development and adult expression-specific mechanisms, has been a greater focus. Within the cerebral landscape, various cell types, such as glia, oligodendrocytes and Purkinje, cerebellar granule and vascular-associated cells express a spectrum of dystrophin isoforms, including Dp427, Dp140, Dp71 and Dp40. The interaction of these isoforms with a multitude of proteins suggests their involvement in neurotransmission, influencing several circuit functions. This review presents the intricate interactions among dystrophin isoforms and diverse protein complexes across different cell types and brain regions, as well as the associated clinical complications. We focus on studies investigating protein interactions with dystrophin in the past 30 years at a biochemical level. In essence, the brain's dystrophin landscape is a thrilling exploration of diversity, challenging preconceptions and opening new avenues for understanding CNS physiology. It also holds potential therapeutic implications for neurological complications involving brain dystrophin deficiency. By revealing the molecular complexities related to dystrophin, this review paves the way for future investigations and therapeutic interventions for this CNS aspect of Duchenne muscular dystrophy.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"1081-1098"},"PeriodicalIF":10.6,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11967788/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The interneuron hypothesis of amyotrophic lateral sclerosis.","authors":"Bryan J Traynor","doi":"10.1093/brain/awaf104","DOIUrl":"10.1093/brain/awaf104","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":"148 4","pages":"1045-1046"},"PeriodicalIF":10.6,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11967792/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Direct interrogation of cortical interneuron circuits in amyotrophic lateral sclerosis.","authors":"Mehdi A J van den Bos, Parvathi Menon, Nathan Pavey, Mana Higashihara, Matthew C Kiernan, Steve Vucic","doi":"10.1093/brain/awae317","DOIUrl":"10.1093/brain/awae317","url":null,"abstract":"<p><p>Cortical hyperexcitability is a key pathogenic feature of amyotrophic lateral sclerosis (ALS), believed to be mediated through complex interplay of cortical interneurons. To date, there has been no technological approach to facilitate the direct capture of cortical interneuron function. Through combination of transcranial magnetic stimulation (TMS) with advanced EEG, the present study examined GABAergic dysfunction in ALS by recording focused cortical output whilst applying TMS over the primary motor cortex contralateral to the site of symptom onset. Using both a single-pulse and a novel inhibitory paired-pulse paradigm, TMS-EEG studies were undertaken on 21 ALS patients and results compared with healthy controls. TMS responses captured by EEG form a discrete waveform known as the transcranial evoked potential (TEP), with positive (P) or upward deflections occurring at 30 (P30), 60 (P60) and 190 ms (P190) after TMS stimulus. Negative (N) or downward deflections occur at 44 (N44), 100 (N100) and 280 ms (N280) after TMS stimulus. The single-pulse TEPs recorded in ALS patients demonstrated novel differences suggestive of cortical GABAergic dysfunction. When compared with controls, the N100 component was significantly reduced (P < 0.05), whereas the P190 component increased (P < 0.05) in ALS patients. Additionally, the N44 component was correlated with muscle weakness (r = -0.501, P < 0.05). These findings were supported by reduced paired-pulse inhibition of TEP components in ALS patients (P60, P < 0.01; N100, P < 0.005), consistent with dysfunction of cortical interneuronal GABAA-ergic circuits. Furthermore, the reduction in short-interval intracortical inhibition, as reflected by changes in paired-pulse inhibition of the N100 component, was associated with longer disease duration in ALS patients (r = -0.698, P < 0.001). In conclusion, intensive and focused interrogation of the motor cortex using novel TMS-EEG combined technologies has established localized dysfunction of GABAergic circuits, supporting the notion that cortical hyperexcitability is mediated by cortical disinhibition in ALS. Dysfunction of GABAergic circuits was correlated with greater clinical disability and disease duration, implying pathophysiological significance.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"1169-1179"},"PeriodicalIF":10.6,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142387838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysregulation of protein SUMOylation networks in Huntington's disease R6/2 mouse striatum.","authors":"Marketta Kachemov, Vineet Vaibhav, Charlene Smith, Niveda Sundararaman, Marie Heath, Devon F Pendlebury, Andrea Matlock, Alice Lau, Eva Morozko, Ryan G Lim, Jack Reidling, Joan S Steffan, Jennifer E Van Eyk, Leslie M Thompson","doi":"10.1093/brain/awae319","DOIUrl":"10.1093/brain/awae319","url":null,"abstract":"<p><p>Huntington's disease is a neurodegenerative disorder caused by an expanded CAG repeat mutation in the Huntingtin (HTT) gene. The mutation impacts neuronal protein homeostasis and cortical/striatal circuitry. SUMOylation is a post-translational modification with broad cellular effects including via modification of synaptic proteins. Here, we used an optimized SUMO protein-enrichment and mass spectrometry method to identify the protein SUMOylation/SUMO interaction proteome in the context of Huntington's disease using R6/2 transgenic and non-transgenic mice. Significant changes in the enrichment of SUMOylated and SUMO-interacting proteins were observed, including those involved in presynaptic function, cytomatrix at the active zone, cytoskeleton organization and glutamatergic signalling. Mitochondrial and RNA-binding proteins also showed altered enrichment. Modified SUMO-associated pathways in Huntington's disease tissue include clathrin-mediated endocytosis signalling, synaptogenesis signalling, synaptic long-term potentiation and SNARE signalling. To evaluate how modulation of SUMOylation might influence functional measures of neuronal activity in Huntington's disease cells in vitro, we used primary neuronal cultures from R6/2 and non-transgenic mice. A receptor internalization assay for the metabotropic glutamate receptor 7 (mGLUR7), a SUMO-enriched protein in the mass spectrometry, showed decreased internalization in R6/2 neurons compared to non-transgenic neurons. SiRNA-mediated knockdown of the E3 SUMO ligase protein inhibitor of activated STAT1 (Pias1), which can SUMO modify mGLUR7, reduced this Huntington's disease phenotype. In addition, microelectrode array analysis of primary neuronal cultures indicated early hyperactivity in Huntington's disease cells, while later time points demonstrated deficits in several measurements of neuronal activity within cortical neurons. Huntington's disease phenotypes were rescued at selected time points following knockdown of Pias1. Collectively, our results provide a mouse brain SUMOome resource and show that significant alterations occur within the post-translational landscape of SUMO-protein interactions of synaptic proteins in Huntington's disease mice, suggesting that targeting of synaptic SUMO networks may provide a proteostatic systems-based therapeutic approach for Huntington's disease and other neurological disorders.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"1212-1227"},"PeriodicalIF":10.6,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11969464/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Plasma p-tau217 in Alzheimer's disease: Lumipulse and ALZpath SIMOA head-to-head comparison.","authors":"","doi":"10.1093/brain/awaf034","DOIUrl":"10.1093/brain/awaf034","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"e29"},"PeriodicalIF":10.6,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11967716/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Visual feature processing in a large stroke cohort: evidence against modular organization.","authors":"Selma Lugtmeijer, Aleksandra M Sobolewska, Edward H F de Haan, H Steven Scholte","doi":"10.1093/brain/awaf009","DOIUrl":"10.1093/brain/awaf009","url":null,"abstract":"<p><p>Mid-level visual processing represents a crucial stage between basic sensory input and higher-level object recognition. The conventional model posits that fundamental visual qualities, such as colour and motion, are processed in specialized, retinotopic brain regions (e.g. V4 for colour, MT/V5 for motion). Using atlas-based lesion-symptom mapping and disconnectome maps in a cohort of 307 ischaemic stroke patients, we examined the neuroanatomical correlates underlying the processing of eight mid-level visual qualities. Contrary to the predictions of the standard model, our results did not reveal consistent relationships between processing impairments and damage to traditionally associated brain regions. Although we validated our methodology by confirming the established relationship between visual field defects and damage to primary visual areas (V1, V2 and V3), we found no reliable evidence linking processing deficits to specific regions in the posterior brain. These findings challenge the traditional modular view of visual processing and suggest that mid-level visual processing might be more distributed across neural networks than previously thought. This supports alternative models where visual maps represent constellations of co-occurring information rather than specific qualities.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"1144-1154"},"PeriodicalIF":10.6,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11969467/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Basal ganglia theta power indexes trait anxiety in people with Parkinson's disease.","authors":"Bart E K S Swinnen, Colin W Hoy, Elena Pegolo, Bryony Ishihara, Elena Ubeda Matzilevich, Julia Sun, Francesca Morgante, Erlick Pereira, Fahd Baig, Michael Hart, Huiling Tan, Zimi Sawacha, Martijn Beudel, Sarah Wang, Philip Starr, Simon Little, Lucia Ricciardi","doi":"10.1093/brain/awae313","DOIUrl":"10.1093/brain/awae313","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Neuropsychiatric symptoms are common and disabling in Parkinson's disease, with troublesome anxiety occurring in one-third of patients. Management of anxiety in Parkinson's disease is challenging, hampered by insufficient insight into underlying mechanisms, lack of objective anxiety measurements and largely ineffective treatments. In this study, we assessed the intracranial neurophysiological correlates of anxiety in patients with Parkinson's disease treated with deep brain stimulation (DBS) in the laboratory and at home. We hypothesized that low-frequency (theta-alpha) activity would be associated with anxiety. We recorded local field potentials from subthalamic nucleus or globus pallidus pars interna DBS implants in three Parkinson's disease cohorts: (i) patients with recordings (subthalamic nucleus) performed in hospital at rest via perioperatively externalized leads, without active stimulation, both ON and OFF dopaminergic medication; (ii) patients with recordings (subthalamic nucleus or globus pallidus pars interna) performed at home while resting, via a chronically implanted commercially available sensing-enabled neurostimulator (Medtronic Percept™ device), ON dopaminergic medication, with stimulation both on and off; and (iii) patients with recordings performed at home while engaging in a behavioural task via subthalamic nucleus and globus pallidus pars interna leads and electrocorticography paddles over the premotor cortex connected to an investigational sensing-enabled neurostimulator, ON dopaminergic medication, with stimulation both on and off. Trait anxiety was measured with validated clinical scales in all participants, and state anxiety was measured with momentary assessment scales at multiple time points in the two at-home cohorts. Power in theta (4-8 Hz) and alpha (8-12 Hz) ranges was extracted from the local field potential recordings, and its relationship with anxiety ratings was assessed using linear mixed-effects models. In total, 33 patients with Parkinson's disease (59 hemispheres) were included. Across three independent cohorts, with stimulation off, basal ganglia theta power was positively related to trait anxiety (all P &lt; 0.05). Also in a naturalistic setting, with individuals at home, at rest, with stimulation and medication ON, basal ganglia theta power was positively related to trait anxiety (P &lt; 0.05). This relationship held regardless of the hemisphere and DBS target. There was no correlation between trait anxiety and premotor cortical theta-alpha power. There was no within-patient association between basal ganglia theta-alpha power and state anxiety. We showed that basal ganglia theta activity indexes trait anxiety in Parkinson's disease. Our data suggest that theta could be a possible physiomarker of neuropsychiatric symptoms and specifically of anxiety in Parkinson's disease, potentially suitable for guiding advanced DBS treatment tailored to the needs of the individual patient, including non-motor symptoms.","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"1228-1241"},"PeriodicalIF":10.6,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7617510/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142457703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SNAP25 variant I67N: synaptic phenotypes, drug response and proteome changes in human neurons","authors":"Maiken Østergaard, Paola Barbagallo, Henriette Reventlow S Frederiksen, Wendy K Chung, Rikke S Møller, Martin Røssel Larsen, Kristine Freude, Matthijs Verhage, Jakob Balslev Sørensen","doi":"10.1093/brain/awaf119","DOIUrl":"https://doi.org/10.1093/brain/awaf119","url":null,"abstract":"SNAREopathies constitute a group of severe genetic neurodevelopmental disorders caused by de novo variants that disturb the synaptic release machinery. These neurodevelopmental disorders comprise highly diverse clinical phenotypes, usually including developmental delay, epilepsy, intellectual disability, and sometimes autism spectrum disorder. Despite major progress in genetic testing, current treatments are limited to symptom-directed therapies. There is an urgent need to establish human experimental systems that improve translatability and help develop personalized mechanisms-based treatment strategies. Here we generated CRISPR/Cas9-engineered human induced pluripotent stem-cell (hiPSC) lines carrying the pathogenic variant I67N in the SNAREopathy gene SNAP25. Using fast forward NGN2-dependent programming into forebrain glutamatergic neurons, we examined synaptic phenotypes using electrophysiology and immunostaining, as well as protein changes by means of proteomics. The variant did not affect passive or active electrical properties, but caused changes in synaptic transmission, including reduced evoked and spontaneous release, decreased synaptic vesicle release probability and consequential changes in short-term plasticity towards facilitation. These phenotypes were distinct from those of human neurons differentiated from hiPSCs originating from a patient carrying the V48F variant, which displayed an increase in spontaneous release. The I67N variant phenotype could be ameliorated by the clinically approved K + -channel blocker 4-aminopyridine. Proteomic analysis of hiPSC-derived neurons revealed a significant enrichment in downregulated synaptic proteins (e.g. CALB1, SCN2A, LRRC4B, PPFIA2). Our study demonstrates the use of hiPSC-based models of neurodevelopmental disorders to identify disease mechanisms and to suggest personalized treatment options directly targeting specific synaptic defects.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"73 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143775529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Traumatic brain injury or head impacts from contact sports are associated with tau astrogliopathy.","authors":"John D Arena, William Stewart, Gabor G Kovacs, Edward B Lee, John L Robinson, Virginia M-Y Lee, John Q Trojanowski, Andrea L C Schneider, Douglas H Smith, Victoria E Johnson","doi":"10.1093/brain/awaf073","DOIUrl":"https://doi.org/10.1093/brain/awaf073","url":null,"abstract":"<p><p>Exposure to traumatic brain injury (TBI) and/or repetitive head impacts (RHI) increases the risk of a range of neurodegenerative pathologies, including chronic traumatic encephalopathy neuropathologic change (CTE-NC). Astrocytic tau pathology reminiscent of aging-related tau astrogliopathy (ARTAG) is a component feature of CTE-NC in many cases. Yet the relationship between TBI/RHI exposure and wider tau astrogliopathy, beyond that of CTE-NC, remains poorly characterized. Autopsy derived material from 556 individuals was selected to include cases with: a history of moderate or severe traumatic brain injury (survival >6 months; n=77) or a history of contact sports participation (n=45); for comparison with uninjured controls with (n=397) or without (n=37) neuropathologically confirmed neurodegenerative disease (NDD). Representative tissue sections from multiple brain regions were then immunostained for hyperphosphorylated tau (p-tau; PHF-1) and assessed in accordance with the harmonized evaluation criteria for ARTAG. PHF-1 immunoreactive thorn-shaped astrocytes (TSA) were observed more frequently in contact sports participants (75.6%) versus controls with (32.5%; p<0.001) and without (8.1%; p<0.001) NDD. In addition, while the prevalence of TSA following moderate/severe TBI (32.5%) was similar to NDD controls, regression analyses demonstrated increased odds of TSA, when adjusting for age and sex (OR 2.42; 95% CI 1.29-4.54). These findings were observed regardless of whether the pathognomonic lesion of CTE-NC was present in the regions examined. Intriguingly, while subpial TSA at sulcal depths were occasionally observed in aged controls with (3.6%) and without (2.8%) NDD, this pathology was considerably more common following RHI/TBI (42.2%; p<0.001). These findings support history of RHI and TBI as independent risk factors for the development of thorn-shaped tau astrogliopathy, over and above ARTAG observed in aging and wider neurodegenerative disease. Moreover, trauma may be associated with TSA within specific distributions, including the subpial region of the cortical sulcal depths. The clinical significance of these observations will be important to determine.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heterozygous RAB3A variants cause cerebellar ataxia by a partial loss-of-function mechanism.","authors":"Holger Hengel, Shabab B Hannan, Selina Reich, Danique Beijer, Johanna Roller, Bernd K Gilsbach, Christian Johannes Gloeckner, Daniel Greene, Dagmar Timmann, Christel Depienne, Andrew Mumford, Mary O'Driscoll, Andrea H Nemeth, Julie Lundberg, Lance H Rodan, Ange-Line Bruel, Julian Delanne, Tine Deconinck, Jonathan Baets, Ziv Gan-Or, Guy Rouleau, Oksana Suchowersky, Mehrdad A Estiar, Stephen Reich, Camilo Toro, Stephan Züchner, Jamilé Hazan, Hjörvar Pétursson, Florian Harmuth, Claudia Bauer, Peter Bauer, Ernest Turro, David Lambright, Ludger Schöls, Matthis Synofzik","doi":"10.1093/brain/awaf111","DOIUrl":"https://doi.org/10.1093/brain/awaf111","url":null,"abstract":"<p><p>RAB3A encodes a small GTP-binding protein that is abundant in brain synaptic vesicles and crucial for the release of neurotransmitters and synaptic plasticity. Here we identified RAB3A as a candidate gene for autosomal dominant cerebellar ataxia by two independent approaches: linkage in a large dominant ataxia family and, in parallel, an untargeted computational genetic association approach, analyzing the 100,000 Genomes Project datasets. To further validate the role of RAB3A in ataxia, we next screened large rare disease databases for rare heterozygous RAB3A variants in probands with ataxia features. In total, we identified 18 individuals from 10 unrelated families all sharing a cerebellar ataxia phenotype. Notably, 9 out of 10 families carried a recurrent variant in RAB3A, p.Arg83Trp, including one de novo occurrence. In addition, our screening revealed three families with a neurodevelopmental phenotype and three unique RAB3A variants, which were either de novo or loss-of-function variants. In line with the different RAB3A variant types, protein domains, and predicted functional consequences, a comprehensive set of complementary methods was used to functionally characterize the identified variants. As expected, GTPase-activating protein (GAP)-dependent GTP hydrolysis was reduced for those two missense variants located in the GAP binding domain of RAB3A (Arg83Trp, Tyr91Cys). In a Drosophila Rab3 loss-of-function model, these two missense variants also failed to rescue a synaptic phenotype. Overexpression of Rab3 variants in Drosophila wildtype background did not cause an obvious phenotype, making a dominant negative effect of these variants unlikely. Lastly, exploring interactors of RAB3A variants by using co-immunoprecipitation and mass spectrometry showed differential changes in variant-specific interactions with known RAB3A key regulatory and effector proteins. In sum, our results establish RAB3A as a neurological disease gene. It represents an autosomal dominant gene for cerebellar ataxia with different variants associated with disease, including the frequent reoccurring variant p.Arg83Trp. Our study sheds light on the variant-specific interactome of RAB3A. Finally, we suggest an association of RAB3A with a neurodevelopmental phenotype, as reported for variants in several RAB3A interaction partners and as seen in Rab3A-deficent mice, although this possible association warrants further investigation by future studies.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}