Sanne M M Vermorgen,Klara Gawor,Sandra O Tomé,Netherlands Brain Bank,Rik Vandenberghe,Christine A F von Arnim,Markus Otto,Philip Van Damme,Jochen H Weishaupt,Annemieke J M Rozemuller,Dietmar Rudolf Thal
Aging-related tau astrogliopathy (ARTAG) refers to aggregates of pathological tau protein in astroglial cells in the brain. Thorny astrocytes at the level of the glia limitans and/or white matter, and granular/fuzzy astrocytes in the grey matter are characteristic for ARTAG, which correlates with aging. However, also rare cases with ARTAG below the age of 66 have been reported. We studied a cohort of 157 brains from donors deceased between 48 and 65 years of age received from the Leuven neuropathological research group and Netherlands Brain Bank in order to gain insight into ARTAG in the medial temporal lobe at younger age, and to find underlying correlates that might be obscured by age-related co-pathologies in older cohorts. Analyses were also performed on two comparison cohorts (Leuven: 268 cases and Netherlands: 397 cases), with ages ranging from 66 to 99 years. Twenty-six out of 157 cases (16.6 %) between 48-65 years had ARTAG, mostly restricted to the medial temporal lobe. Only 6 cases exhibited ARTAG in lobar regions. ARTAG was found in all 5 previously described morphologies and locations: subpial, subependymal, perivascular, white matter and grey matter. In our young cohort, a significant correlation was found between ARTAG and the presence of neurodegenerative conditions of any kind and between ARTAG and age. When correcting for age and sex, the association between ARTAG and the presence of neurodegenerative conditions was upheld. There were no significant associations between ARTAG and specific proteinopathies, though trends were observed for α-synucleinopathy, Tauopathy and TDP-43 proteinopathy diagnoses. The presence of lobar ARTAG was related to ARTAG severity in the young cohort. In the older cohorts, only age was significantly associated with ARTAG. These results suggest a link between ARTAG in the medial temporal lobe of young individuals and pathological protein aggregation of any kind in the brain independent of age and might raise the question whether ARTAG points to astrocytes as important players for selective vulnerability for the aggregation of pathological proteins in distinct brain regions in this patient population.
{"title":"Medial temporal ageing-related tau astrogliopathy below 66 years is associated with neurodegeneration.","authors":"Sanne M M Vermorgen,Klara Gawor,Sandra O Tomé,Netherlands Brain Bank,Rik Vandenberghe,Christine A F von Arnim,Markus Otto,Philip Van Damme,Jochen H Weishaupt,Annemieke J M Rozemuller,Dietmar Rudolf Thal","doi":"10.1093/brain/awag011","DOIUrl":"https://doi.org/10.1093/brain/awag011","url":null,"abstract":"Aging-related tau astrogliopathy (ARTAG) refers to aggregates of pathological tau protein in astroglial cells in the brain. Thorny astrocytes at the level of the glia limitans and/or white matter, and granular/fuzzy astrocytes in the grey matter are characteristic for ARTAG, which correlates with aging. However, also rare cases with ARTAG below the age of 66 have been reported. We studied a cohort of 157 brains from donors deceased between 48 and 65 years of age received from the Leuven neuropathological research group and Netherlands Brain Bank in order to gain insight into ARTAG in the medial temporal lobe at younger age, and to find underlying correlates that might be obscured by age-related co-pathologies in older cohorts. Analyses were also performed on two comparison cohorts (Leuven: 268 cases and Netherlands: 397 cases), with ages ranging from 66 to 99 years. Twenty-six out of 157 cases (16.6 %) between 48-65 years had ARTAG, mostly restricted to the medial temporal lobe. Only 6 cases exhibited ARTAG in lobar regions. ARTAG was found in all 5 previously described morphologies and locations: subpial, subependymal, perivascular, white matter and grey matter. In our young cohort, a significant correlation was found between ARTAG and the presence of neurodegenerative conditions of any kind and between ARTAG and age. When correcting for age and sex, the association between ARTAG and the presence of neurodegenerative conditions was upheld. There were no significant associations between ARTAG and specific proteinopathies, though trends were observed for α-synucleinopathy, Tauopathy and TDP-43 proteinopathy diagnoses. The presence of lobar ARTAG was related to ARTAG severity in the young cohort. In the older cohorts, only age was significantly associated with ARTAG. These results suggest a link between ARTAG in the medial temporal lobe of young individuals and pathological protein aggregation of any kind in the brain independent of age and might raise the question whether ARTAG points to astrocytes as important players for selective vulnerability for the aggregation of pathological proteins in distinct brain regions in this patient population.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"30 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145995003","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}
Cerebral cavernous malformations are common vascular anomalies in the central nervous system that predispose individuals to seizures and hemorrhagic stroke. Familial forms are linked to germline loss-of-function mutations in CCM1-3, and sporadic lesions frequently harbor somatic gain-of-function mutations in MAP3K3 and PIK3CA. However, the mechanisms by which these somatic mutations drive lesion development remain incompletely understood, and no medical therapies are currently available. Here, we investigated the cooperative effects of MAP3K3I441M and PIK3CAH1047R mutations using transgenic neonatal and adult mouse model, supported by histology, micro-CT, bulk and single-cell RNA sequencing, and human cerebral cavernous malformations samples. MAP3K3 I441M activated inflammatory and angiogenic transcriptional programs in brain endothelial cells, whereas PIK3CAH1047R enhanced cell cycle and DNA replication pathways. Notably, MAP3K3I441M and PIK3CAH1047R double mutations synergistically amplified PI3K-AKT-mTOR signaling, inducing an "angiogenic switch" reminiscent of tumor neovascularization. This interaction promoted endothelial angiogenesis and lesion development in mouse brains. Transcriptomic analyses of human cerebral cavernous malformations confirmed enrichment of angiogenesis-related gene signatures in double mutations-related lesions. Treatment with the PI3Kα-selective inhibitor alpelisib suppressed lesion formation and reversed pro-angiogenic signaling in both mouse models and patient-derived cerebral cavernous malformations organoids. These findings uncover a convergent mechanism involving MAPK and PI3K pathway activation in cerebral cavernous malformations pathogenesis and demonstrate that PI3Kα inhibition may offer a viable therapeutic strategy for a disease that currently lacks effective pharmacological treatment.
{"title":"Angiogenic switching in cerebral cavernous malformations driven by MAP3K3-PIK3CA synergy.","authors":"Jian Ren,Yeqing Ren,An Tian,Ziwei Cui,Daochao Wang,Hao Yu,Chendan Jiang,Jiaxing Yu,Shikun Zhang,Jing Chen,Shuang Liang,Yu Gu,Yiqing Wang,Jianfeng Lei,Xiangjian Zheng,Dong Xing,Hongqi Zhang,Tao Hong","doi":"10.1093/brain/awag017","DOIUrl":"https://doi.org/10.1093/brain/awag017","url":null,"abstract":"Cerebral cavernous malformations are common vascular anomalies in the central nervous system that predispose individuals to seizures and hemorrhagic stroke. Familial forms are linked to germline loss-of-function mutations in CCM1-3, and sporadic lesions frequently harbor somatic gain-of-function mutations in MAP3K3 and PIK3CA. However, the mechanisms by which these somatic mutations drive lesion development remain incompletely understood, and no medical therapies are currently available. Here, we investigated the cooperative effects of MAP3K3I441M and PIK3CAH1047R mutations using transgenic neonatal and adult mouse model, supported by histology, micro-CT, bulk and single-cell RNA sequencing, and human cerebral cavernous malformations samples. MAP3K3 I441M activated inflammatory and angiogenic transcriptional programs in brain endothelial cells, whereas PIK3CAH1047R enhanced cell cycle and DNA replication pathways. Notably, MAP3K3I441M and PIK3CAH1047R double mutations synergistically amplified PI3K-AKT-mTOR signaling, inducing an \"angiogenic switch\" reminiscent of tumor neovascularization. This interaction promoted endothelial angiogenesis and lesion development in mouse brains. Transcriptomic analyses of human cerebral cavernous malformations confirmed enrichment of angiogenesis-related gene signatures in double mutations-related lesions. Treatment with the PI3Kα-selective inhibitor alpelisib suppressed lesion formation and reversed pro-angiogenic signaling in both mouse models and patient-derived cerebral cavernous malformations organoids. These findings uncover a convergent mechanism involving MAPK and PI3K pathway activation in cerebral cavernous malformations pathogenesis and demonstrate that PI3Kα inhibition may offer a viable therapeutic strategy for a disease that currently lacks effective pharmacological treatment.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"9 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145995002","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}
Raphael Reinecke, Sophie Nitsch, Francisca Faber, Cansu Elmas, Marlene Gaubinger, Anika Simonovska Serra, Verena Endmayr, Inga Koneczny, Evelyn Berger-Sieczkowski, Morten Blaabjerg, M Elena Erro, Julia Ferrari, Markus Glatzel, Anna Heidbreder, Birgit Högl, Casper Jansen, Jan Lewerenz, Patrizia Moser, Liisa Myllykangas, Jeanette Krogh Petersen, Peter Schnider, Ambra Stefani, Maarten J Titulaer, Deniz Yilmazer-Hanke, Serge Weis, Lidia Sabater, Carles Gaig, Ellen Gelpi, Romana Höftberger
Anti-IgLON5 disease is a rare neurological disease at the intersection of autoimmunity and neurodegeneration. It is characterized by the presence of anti-IgLON5 antibodies and the development of a brainstem-dominant tau pathology. Recent research indicates that the tau pathology may develop in a time-dependent manner. A three-staged neuropathological classification of the disease has been recently suggested, ranging from no or minimal tau (stage 1) to the characteristic brainstem tau pathology (stage 3) as originally described. This study aimed to characterize the evolution of the disease-associated tauopathy more precisely and to further investigate the early neurodegenerative events in anti-IgLON5 disease. We analyzed the medullary region of 14 autopsy cases of anti-IgLON5 disease with different severity grades of tau pathology and varying disease durations, from 6 to 180 months, and compared our findings with five PSP cases and ten neurologically healthy controls by immunohistochemistry. We applied a broad panel of antibodies targeting different pathological tau post-translational modification sites and the nuclear membrane. In addition, we performed a cell culture of rat hippocampal neurons incubated with purified anti-IgLON5 antibodies to validate the results of the autopsy samples. Based on the tau burden in relation to the pathology stage and disease duration, we determined the chronological appearance of the different post-translational modifications of tau. Phosphorylation at Serine 422 was identified as one of the first alterations at stage 1 and showed an early neuronal nuclear staining with simultaneous anti-IgLON5 IgG4 deposits on the neuronal surface as observed by double immunolabeling. Nuclear membrane alterations were also evident by Lamin B1 staining. These were significantly more frequent at stage 1 as compared to controls and adopted the form of nuclear invaginations and crenellations. Crenellations of the nuclear membrane also developed in neuronal cell culture after three weeks of antibody incubation, supporting the autopsy findings in vitro. The development of cytoplasmic tau pathology occurs at later stages of the disease with a sequence of post-translational modifications, after an initial nuclear pathology. These new findings contribute to a better understanding of the early pathophysiological events in anti-IgLON5 disease and reinforce the concept of a secondary tauopathy related to an immune-mediated mechanism.
{"title":"Brainstem pathology in anti-IgLON5 disease: new insights into early events and tau progression","authors":"Raphael Reinecke, Sophie Nitsch, Francisca Faber, Cansu Elmas, Marlene Gaubinger, Anika Simonovska Serra, Verena Endmayr, Inga Koneczny, Evelyn Berger-Sieczkowski, Morten Blaabjerg, M Elena Erro, Julia Ferrari, Markus Glatzel, Anna Heidbreder, Birgit Högl, Casper Jansen, Jan Lewerenz, Patrizia Moser, Liisa Myllykangas, Jeanette Krogh Petersen, Peter Schnider, Ambra Stefani, Maarten J Titulaer, Deniz Yilmazer-Hanke, Serge Weis, Lidia Sabater, Carles Gaig, Ellen Gelpi, Romana Höftberger","doi":"10.1093/brain/awag015","DOIUrl":"https://doi.org/10.1093/brain/awag015","url":null,"abstract":"Anti-IgLON5 disease is a rare neurological disease at the intersection of autoimmunity and neurodegeneration. It is characterized by the presence of anti-IgLON5 antibodies and the development of a brainstem-dominant tau pathology. Recent research indicates that the tau pathology may develop in a time-dependent manner. A three-staged neuropathological classification of the disease has been recently suggested, ranging from no or minimal tau (stage 1) to the characteristic brainstem tau pathology (stage 3) as originally described. This study aimed to characterize the evolution of the disease-associated tauopathy more precisely and to further investigate the early neurodegenerative events in anti-IgLON5 disease. We analyzed the medullary region of 14 autopsy cases of anti-IgLON5 disease with different severity grades of tau pathology and varying disease durations, from 6 to 180 months, and compared our findings with five PSP cases and ten neurologically healthy controls by immunohistochemistry. We applied a broad panel of antibodies targeting different pathological tau post-translational modification sites and the nuclear membrane. In addition, we performed a cell culture of rat hippocampal neurons incubated with purified anti-IgLON5 antibodies to validate the results of the autopsy samples. Based on the tau burden in relation to the pathology stage and disease duration, we determined the chronological appearance of the different post-translational modifications of tau. Phosphorylation at Serine 422 was identified as one of the first alterations at stage 1 and showed an early neuronal nuclear staining with simultaneous anti-IgLON5 IgG4 deposits on the neuronal surface as observed by double immunolabeling. Nuclear membrane alterations were also evident by Lamin B1 staining. These were significantly more frequent at stage 1 as compared to controls and adopted the form of nuclear invaginations and crenellations. Crenellations of the nuclear membrane also developed in neuronal cell culture after three weeks of antibody incubation, supporting the autopsy findings in vitro. The development of cytoplasmic tau pathology occurs at later stages of the disease with a sequence of post-translational modifications, after an initial nuclear pathology. These new findings contribute to a better understanding of the early pathophysiological events in anti-IgLON5 disease and reinforce the concept of a secondary tauopathy related to an immune-mediated mechanism.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"37 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986488","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}
Aleksandra Beric,Sarp Sahin,Santiago Sanchez,Zining Yang,Ravindra Kumar,Isabel Alfradique-Dunham,Jessie Sanford,Daniel Western,Bridget Phillips,John P Budde,Richard J Perrin,Paul T Kotzbauer,Joel S Perlmutter,Scott A Norris,Carlos Cruchaga,Laura Ibanez
Parkinson's disease is the second leading neurodegenerative disease, pathologically characterized by the accumulation of alpha-synuclein in the brain and the loss of dopaminergic neurons in the substantia nigra pars compacta. Despite the intensive efforts to identify diagnostic biomarkers for Parkinson's disease nominating prospective candidates such as such as CSF α-synuclein seed amplification assay or α-/β-synuclein ratio, establishment of minimally invasive biomarkers remains the focus of Parkinson's disease research. We leveraged transcriptomic data from 4,343 participants from four independent datasets to robustly identify Parkinson's disease-associated transcripts. Following the differential abundance analyses, we integrated our findings with several brain transcriptomic, CSF proteomic, plasma proteomic and genomic data to add biological context. We further leveraged our findings to develop predictive models that could differentiate between Parkinson's disease and healthy controls. We identified 296 differentially expressed transcripts, 28 of which were transcribed from known Parkinson's disease-associated loci. Further, we found a significant overlap between our findings and transcripts dysregulated in brain, as well as proteins differentially accumulated in CSF. Our results suggest that expression of the identified transcripts was affected by genetic background including ancestry and Parkinson's disease-related mutations, and nearly half of the identified transcripts were dysregulated before symptom onset. The differentially expressed transcripts were utilized to develop three predictive models that distinguished between Parkinson's disease and healthy controls with a ROC AUC of 0.727-0.733. The predictive models were capable of detecting Parkinson's disease transcriptomic signatures even before symptom onset. Overall, two transcripts, DLD and CD55, showed particular promise as early stage, minimally invasive Parkinson's disease biomarkers. DLD significantly related to Parkinson's disease in the eQTL analyses and we identified a suggestive eQTL for CD55, their protein products were differentially accumulated in CSF, and both DLD and CD55 were included in all three predictive models. Thus, we have performed the largest Parkinson's disease transcriptomic study to date and demonstrated that the transcriptome can be leveraged for development of minimally invasive biomarkers that could aid in diagnosing Parkinson's disease.
{"title":"Study of blood linear RNA nominates CD55 and DLD as early-stage biomarkers for Parkinson's sisease.","authors":"Aleksandra Beric,Sarp Sahin,Santiago Sanchez,Zining Yang,Ravindra Kumar,Isabel Alfradique-Dunham,Jessie Sanford,Daniel Western,Bridget Phillips,John P Budde,Richard J Perrin,Paul T Kotzbauer,Joel S Perlmutter,Scott A Norris,Carlos Cruchaga,Laura Ibanez","doi":"10.1093/brain/awag014","DOIUrl":"https://doi.org/10.1093/brain/awag014","url":null,"abstract":"Parkinson's disease is the second leading neurodegenerative disease, pathologically characterized by the accumulation of alpha-synuclein in the brain and the loss of dopaminergic neurons in the substantia nigra pars compacta. Despite the intensive efforts to identify diagnostic biomarkers for Parkinson's disease nominating prospective candidates such as such as CSF α-synuclein seed amplification assay or α-/β-synuclein ratio, establishment of minimally invasive biomarkers remains the focus of Parkinson's disease research. We leveraged transcriptomic data from 4,343 participants from four independent datasets to robustly identify Parkinson's disease-associated transcripts. Following the differential abundance analyses, we integrated our findings with several brain transcriptomic, CSF proteomic, plasma proteomic and genomic data to add biological context. We further leveraged our findings to develop predictive models that could differentiate between Parkinson's disease and healthy controls. We identified 296 differentially expressed transcripts, 28 of which were transcribed from known Parkinson's disease-associated loci. Further, we found a significant overlap between our findings and transcripts dysregulated in brain, as well as proteins differentially accumulated in CSF. Our results suggest that expression of the identified transcripts was affected by genetic background including ancestry and Parkinson's disease-related mutations, and nearly half of the identified transcripts were dysregulated before symptom onset. The differentially expressed transcripts were utilized to develop three predictive models that distinguished between Parkinson's disease and healthy controls with a ROC AUC of 0.727-0.733. The predictive models were capable of detecting Parkinson's disease transcriptomic signatures even before symptom onset. Overall, two transcripts, DLD and CD55, showed particular promise as early stage, minimally invasive Parkinson's disease biomarkers. DLD significantly related to Parkinson's disease in the eQTL analyses and we identified a suggestive eQTL for CD55, their protein products were differentially accumulated in CSF, and both DLD and CD55 were included in all three predictive models. Thus, we have performed the largest Parkinson's disease transcriptomic study to date and demonstrated that the transcriptome can be leveraged for development of minimally invasive biomarkers that could aid in diagnosing Parkinson's disease.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"29 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956197","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}
Despite multiple available strategies for managing motor fluctuations in advanced Parkinson's disease, there is a continuing need for improved therapeutics. After 2-5 years of levodopa treatment, some patients start to experience OFF time that can occupy five or more hours/day. Responding to this challenge are pump-delivered infusion therapies for delivering carbidopa-levodopa or apomorphine. However, despite their ability to provide continuous dopaminergic stimulation, these options generally do not provide fluctuators with full control of daily OFF time. The complexity of managing motor fluctuations is further highlighted by the effectiveness of various non-dopaminergic adjunctive therapies for reducing OFF time in levodopa-treated patients, as shown by placebo-controlled clinical trials with adjunctive istradefylline, amantadine, zonisamide, and deep brain stimulation. Other recent paradigm shifts for understanding levodopa's role in Parkinson's disease therapeutics are observations that reserpine-induced Parkinsonism in mice can be reversed without its conversion to dopamine. For achieving better control of OFF time in advanced Parkinson's disease, there is a need for discovering therapeutic strategies acting beyond the limits of today's dopaminergic therapies. Modeling brain circuitry with tools like deterministic neural-computational analysis may provide valuable pharmacological and electrophysiological insights for better understanding of motor fluctuations and the choice of appropriate therapeutic targets.
{"title":"The persisting puzzle of OFF time in advanced Parkinson's disease.","authors":"Peter A LeWitt","doi":"10.1093/brain/awag002","DOIUrl":"https://doi.org/10.1093/brain/awag002","url":null,"abstract":"Despite multiple available strategies for managing motor fluctuations in advanced Parkinson's disease, there is a continuing need for improved therapeutics. After 2-5 years of levodopa treatment, some patients start to experience OFF time that can occupy five or more hours/day. Responding to this challenge are pump-delivered infusion therapies for delivering carbidopa-levodopa or apomorphine. However, despite their ability to provide continuous dopaminergic stimulation, these options generally do not provide fluctuators with full control of daily OFF time. The complexity of managing motor fluctuations is further highlighted by the effectiveness of various non-dopaminergic adjunctive therapies for reducing OFF time in levodopa-treated patients, as shown by placebo-controlled clinical trials with adjunctive istradefylline, amantadine, zonisamide, and deep brain stimulation. Other recent paradigm shifts for understanding levodopa's role in Parkinson's disease therapeutics are observations that reserpine-induced Parkinsonism in mice can be reversed without its conversion to dopamine. For achieving better control of OFF time in advanced Parkinson's disease, there is a need for discovering therapeutic strategies acting beyond the limits of today's dopaminergic therapies. Modeling brain circuitry with tools like deterministic neural-computational analysis may provide valuable pharmacological and electrophysiological insights for better understanding of motor fluctuations and the choice of appropriate therapeutic targets.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"66 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145955977","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}
Mohamed F Ibrahim,Sevda Boyanova,Yin Chun Cheng,Clemence Ligneul,Rasneer S Bains,Tiffany C Johnpulle,Jason P Lerch,Edward O Mann,Peter L Oliver,Esther B E Becker
Spinocerebellar ataxias (SCAs) are autosomal dominantly inherited neurodegenerative disorders with no effective treatment. Aberrant signalling through the metabotropic glutamate receptor (mGluR1) has been implicated in several SCAs. However, whether disease is caused through decreased or increased mGluR1 signalling remains controversial. Here, we generate the first mouse model of enhanced mGluR1 function by introducing a gain-of-function mutation (p.Y792C) that causes SCA44 in the metabotropic glutamate receptor 1 (Grm1) gene. Grm1 mutant mice recapitulate key pathophysiological aspects of SCA, including progressive motor deficits, altered climbing fibre innervation and perturbed Purkinje cell (PC) spontaneous activity. We report that changes in synaptic innervation and intrinsic PC activity upon overactive mGluR1 signalling manifest in a lobule- and disease-stage-specific manner. Our findings demonstrate that enhanced mGluR1 function is a direct and specific driver of PC dysfunction and pathology and provide a mechanism for understanding the selective vulnerability of different PC populations in SCA.
{"title":"Enhanced mGluR1 function causes motor deficits and region-specific Purkinje cell dysfunction.","authors":"Mohamed F Ibrahim,Sevda Boyanova,Yin Chun Cheng,Clemence Ligneul,Rasneer S Bains,Tiffany C Johnpulle,Jason P Lerch,Edward O Mann,Peter L Oliver,Esther B E Becker","doi":"10.1093/brain/awaf477","DOIUrl":"https://doi.org/10.1093/brain/awaf477","url":null,"abstract":"Spinocerebellar ataxias (SCAs) are autosomal dominantly inherited neurodegenerative disorders with no effective treatment. Aberrant signalling through the metabotropic glutamate receptor (mGluR1) has been implicated in several SCAs. However, whether disease is caused through decreased or increased mGluR1 signalling remains controversial. Here, we generate the first mouse model of enhanced mGluR1 function by introducing a gain-of-function mutation (p.Y792C) that causes SCA44 in the metabotropic glutamate receptor 1 (Grm1) gene. Grm1 mutant mice recapitulate key pathophysiological aspects of SCA, including progressive motor deficits, altered climbing fibre innervation and perturbed Purkinje cell (PC) spontaneous activity. We report that changes in synaptic innervation and intrinsic PC activity upon overactive mGluR1 signalling manifest in a lobule- and disease-stage-specific manner. Our findings demonstrate that enhanced mGluR1 function is a direct and specific driver of PC dysfunction and pathology and provide a mechanism for understanding the selective vulnerability of different PC populations in SCA.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"4 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956198","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":"Occludin takes centre stage in HIV defence and stroke.","authors":"Amber Douglass,Clarissa Halpern,Sanjay B Maggirwa","doi":"10.1093/brain/awag013","DOIUrl":"https://doi.org/10.1093/brain/awag013","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":"45 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937844","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":"Risk, reward or repetition? New data on human ventral tegmental area stimulation challenge dominant frameworks.","authors":"Luke Clark,Catharine A Winstanley","doi":"10.1093/brain/awag012","DOIUrl":"https://doi.org/10.1093/brain/awag012","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":"97 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937843","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}
The progressive age-related aggregation of soluble α-synuclein into toxic oligomers and insoluble amyloid fibrils causes Parkinson's disease, Lewy body dementia, and multiple system atrophy, which are all neurodegenerative diseases without a cure. Because α-synuclein is a self-antigen, pathogenic α-synuclein aggregates do not elicit a strong immune response. Recent advances in structural biology elucidating the structure of α-synuclein fibrils have allowed us to design engineered protein fibrils that model conformational epitopes present on the surface of α-synuclein fibrils. HET-s is a soluble fungal protein capable of forming amyloid fibrils. We used HET-s(218-298) fibrils and four modified derivatives, each displaying a selected conformational epitope present on the surface of α-synuclein fibrils, to vaccinate TgM83+/- mice, a model for Parkinson's disease-like synucleinopathies. Fibrillar vaccine candidates significantly extended the survival of immunized TgM83+/- mice by up to 38% after intraperitoneal challenge and 42% after intragastric challenge with α-synuclein fibrils. Fully immunized mice had developed antibodies that recognized α-synuclein fibrils and brain homogenates from patients with dementia with Lewy bodies, multiple system atrophy, and Parkinson's disease. Fibrillar vaccine candidates that mimic conformational epitopes on the surface of pathological α-synuclein fibrils have the ability to induce immunity and protection against Parkinson's disease and other synucleinopathies.
{"title":"Vaccines mimicking conformational epitopes on α-synuclein fibrils provide immunity to Parkinson's disease.","authors":"Liang Ma,Sara Reithofer,Verena Pesch,José Miguel Flores-Fernandez,Aishwarya Sriraman,Caleb Duckering,Sara Amidian,Pelin Özdüzenciler,Laura Müller,Holger Wille,Gültekin Tamgüney","doi":"10.1093/brain/awag010","DOIUrl":"https://doi.org/10.1093/brain/awag010","url":null,"abstract":"The progressive age-related aggregation of soluble α-synuclein into toxic oligomers and insoluble amyloid fibrils causes Parkinson's disease, Lewy body dementia, and multiple system atrophy, which are all neurodegenerative diseases without a cure. Because α-synuclein is a self-antigen, pathogenic α-synuclein aggregates do not elicit a strong immune response. Recent advances in structural biology elucidating the structure of α-synuclein fibrils have allowed us to design engineered protein fibrils that model conformational epitopes present on the surface of α-synuclein fibrils. HET-s is a soluble fungal protein capable of forming amyloid fibrils. We used HET-s(218-298) fibrils and four modified derivatives, each displaying a selected conformational epitope present on the surface of α-synuclein fibrils, to vaccinate TgM83+/- mice, a model for Parkinson's disease-like synucleinopathies. Fibrillar vaccine candidates significantly extended the survival of immunized TgM83+/- mice by up to 38% after intraperitoneal challenge and 42% after intragastric challenge with α-synuclein fibrils. Fully immunized mice had developed antibodies that recognized α-synuclein fibrils and brain homogenates from patients with dementia with Lewy bodies, multiple system atrophy, and Parkinson's disease. Fibrillar vaccine candidates that mimic conformational epitopes on the surface of pathological α-synuclein fibrils have the ability to induce immunity and protection against Parkinson's disease and other synucleinopathies.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"27 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937846","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}
Camila Armirola-Ricaurte, Laura Morant, Isabelle Adant, Sherifa A Hamed, Menelaos Pipis, Stephanie Efthymiou, Silvia Amor-Barris, Derek Atkinson, Liedewei Van de Vondel, Aleksandra Tomic, Sara Seneca, Els de Vriendt, Stephan Zuchner, Bart Ghesquiere, Michael G Hanna, Henry Houlden, Michael P Lunn, Mary M Reilly, Vedrana Milic Rasic, Albena Jordanova
Defects in mitochondrial dynamics are a common cause of Charcot-Marie-Tooth disease (CMT), whereas primary deficiencies in the mitochondrial respiratory chain (MRC) are rare and atypical for this aetiology. This study aims to report COX18 as a novel CMT-causing gene. This gene encodes an assembly factor of mitochondrial Complex IV that translocates the C-terminal tail of MTCO2 across the mitochondrial inner membrane. Exome sequencing was performed in four affected individuals from three families. The patients and available family members underwent thorough neurological and electrophysiological assessment. The impact of one of the identified variants on splicing, protein levels and mitochondrial bioenergetics was investigated in patient-derived lymphoblasts. The functionality of the mutant protein was assessed using a proteinase K protection assay and immunoblotting. Neuronal relevance of COX18 was assessed in a Drosophila melanogaster knockdown model. Exome sequencing coupled with homozygosity mapping revealed a homozygous splice variant c.435-6A>G in COX18 in two siblings with early-onset progressive axonal sensorimotor peripheral neuropathy. By querying external databases, we identified two additional families with rare deleterious biallelic variants in COX18. All eight affected individuals presented with axonal CMT, and some patients also exhibited CNS symptoms, such as dystonia and spasticity. Functional characterization of the c.435-6A>G variant demonstrated that it leads to the expression of an alternative transcript that lacks exon 2, resulting in a stable but defective COX18 isoform. The mutant protein impairs Complex IV assembly and activity, leading to a reduction in mitochondrial membrane potential. Downregulation of the COX18 homologue in D. melanogaster resulted in signs of neurodegeneration, including locomotor deficit and progressive axonal degeneration of sensory neurons. Our study presents genetic and functional evidence that supports COX18 as a newly identified gene candidate for autosomal recessive axonal CMT with or without CNS involvement. These findings emphasize the significance of peripheral neuropathy within the spectrum of primary mitochondrial disorders, in addition to the role of mitochondrial Complex IV in the development of CMT. Our research has important implications for the diagnostic work-up of CMT patients.
{"title":"Biallelic variants in COX18 cause a mitochondrial disorder primarily manifesting as peripheral neuropathy.","authors":"Camila Armirola-Ricaurte, Laura Morant, Isabelle Adant, Sherifa A Hamed, Menelaos Pipis, Stephanie Efthymiou, Silvia Amor-Barris, Derek Atkinson, Liedewei Van de Vondel, Aleksandra Tomic, Sara Seneca, Els de Vriendt, Stephan Zuchner, Bart Ghesquiere, Michael G Hanna, Henry Houlden, Michael P Lunn, Mary M Reilly, Vedrana Milic Rasic, Albena Jordanova","doi":"10.1093/brain/awaf300","DOIUrl":"10.1093/brain/awaf300","url":null,"abstract":"<p><p>Defects in mitochondrial dynamics are a common cause of Charcot-Marie-Tooth disease (CMT), whereas primary deficiencies in the mitochondrial respiratory chain (MRC) are rare and atypical for this aetiology. This study aims to report COX18 as a novel CMT-causing gene. This gene encodes an assembly factor of mitochondrial Complex IV that translocates the C-terminal tail of MTCO2 across the mitochondrial inner membrane. Exome sequencing was performed in four affected individuals from three families. The patients and available family members underwent thorough neurological and electrophysiological assessment. The impact of one of the identified variants on splicing, protein levels and mitochondrial bioenergetics was investigated in patient-derived lymphoblasts. The functionality of the mutant protein was assessed using a proteinase K protection assay and immunoblotting. Neuronal relevance of COX18 was assessed in a Drosophila melanogaster knockdown model. Exome sequencing coupled with homozygosity mapping revealed a homozygous splice variant c.435-6A>G in COX18 in two siblings with early-onset progressive axonal sensorimotor peripheral neuropathy. By querying external databases, we identified two additional families with rare deleterious biallelic variants in COX18. All eight affected individuals presented with axonal CMT, and some patients also exhibited CNS symptoms, such as dystonia and spasticity. Functional characterization of the c.435-6A>G variant demonstrated that it leads to the expression of an alternative transcript that lacks exon 2, resulting in a stable but defective COX18 isoform. The mutant protein impairs Complex IV assembly and activity, leading to a reduction in mitochondrial membrane potential. Downregulation of the COX18 homologue in D. melanogaster resulted in signs of neurodegeneration, including locomotor deficit and progressive axonal degeneration of sensory neurons. Our study presents genetic and functional evidence that supports COX18 as a newly identified gene candidate for autosomal recessive axonal CMT with or without CNS involvement. These findings emphasize the significance of peripheral neuropathy within the spectrum of primary mitochondrial disorders, in addition to the role of mitochondrial Complex IV in the development of CMT. Our research has important implications for the diagnostic work-up of CMT patients.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"178-193"},"PeriodicalIF":11.7,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12782158/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144882090","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：