Mark Walton argues that while the UK has a long and distinguished record of supporting brain research, this now risks being eroded by funding insufficiencies, career insecurity, and excessive bureaucracy. These pressures threaten to undermine morale and jeopardize the UK’s status as a global leader in this field.
{"title":"Gradually, then suddenly: the precarious position of UK preclinical neuroscience","authors":"Mark E Walton","doi":"10.1093/brain/awag030","DOIUrl":"https://doi.org/10.1093/brain/awag030","url":null,"abstract":"Mark Walton argues that while the UK has a long and distinguished record of supporting brain research, this now risks being eroded by funding insufficiencies, career insecurity, and excessive bureaucracy. These pressures threaten to undermine morale and jeopardize the UK’s status as a global leader in this field.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"90 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146101323","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}
Paolo A Muraro, Eleonora De Matteis, Antonio Scalfari
This scientific commentary refers to ‘Haematopoietic stem cell transplant versus immune-reconstitution therapy in relapsing multiple sclerosis’ by Kalincik et al. (https://doi.org/10.1093/brain/awaf286).
{"title":"A tight match: comparing the effectiveness of immune reconstitution therapies for multiple sclerosis","authors":"Paolo A Muraro, Eleonora De Matteis, Antonio Scalfari","doi":"10.1093/brain/awag044","DOIUrl":"https://doi.org/10.1093/brain/awag044","url":null,"abstract":"This scientific commentary refers to ‘Haematopoietic stem cell transplant versus immune-reconstitution therapy in relapsing multiple sclerosis’ by Kalincik et al. (https://doi.org/10.1093/brain/awaf286).","PeriodicalId":9063,"journal":{"name":"Brain","volume":"29 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146101322","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}
Wenchao Shao, Daniel V Oliveira, Luana Naia, Yue Li, Katrine Dahl Bjørnholm, Arturo G Isla, Per Uhlén, Raj Kalaria, Saskia A J Lesnik Oberstein, Urban Lendahl, Luis EnriqueArroyo-García, ShaoBo Jin, Helena Karlström
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a small vessel disease caused by cysteine-altering NOTCH3 gene variants, leading to vascular smooth muscle cell degeneration, compromised cerebral blood flow, subcortical ischemic infarcts, cognitive decline, and often ultimately vascular dementia. Little is known about the cellular and molecular effects downstream of the cerebral ischemia in CADASIL, or whether brain regions known to be involved in dementia, such as the hippocampus, are particularly susceptible to such pathological downstream changes. In this study, we used a humanized CADASIL mouse model harbouring the p.(Arg182Cys) variant (R182C-TgN3), post-mortem human CADASIL brain sections with four different NOTCH3 gene variants and primary human cerebral vascular smooth muscle cells (VSMCs) harbouring the p.R133C NOTCH3 variant as primary cellular models to characterise the properties and contribution of mutant VSMCs to cognitive impairment. To specifically evaluate neuronal, mitochondrial and neurovascular function, we performed ex vivo electrophysiology, immunohistochemistry (confocal and iDISCO+ methods), western blotting, Seahorse assay, quantitative polymerase chain reaction (qPCR), and single-cell RNA sequencing. In the CADASIL mice, hippocampal gamma oscillation patterns were impaired along with significant decreases in neuronal fiber length and aberrant neuronal morphology. The latter two phenotypes were also observed in post-mortem brain tissue from CADASIL patients. Consistent with these findings, we noted significantly lower levels of mitochondrial respiratory complexes in the CADASIL mouse hippocampus, isolated mouse brain vessels and primary human cerebral VSMCs. The human cerebral VSMCs exhibited reduced oxygen consumption rates leading to reduced ATP production as well as decreased glycolytic capacity in conjunction with increased pro-inflammatory gene expression, suggesting a broader impact on cellular energy metabolism and a neuroinflammatory process. In the CADASIL mice, we also observed extensive accumulation of the NOTCH3 extracellular domain in hippocampal vessels. Light sheet imaging with iDISCO+ clearing demonstrated substantial VSMC loss and reduced vessel density in the hippocampus at 9 months of age. Additionally, 3D imaging showed increased microglial attachment to vessels and enlargement of the size of the vessel-associated microglia in CADASIL mice. Single-cell RNA sequencing revealed a microglial subcluster expressing genes involved in mitochondrial respiration and inflammation. Collectively, our results reveal how small vessel pathology in CADASIL leads to significant neuronal pathology in the hippocampus involving metabolic and neuroinflammatory changes and highlight the critical role of the neurovascular unit. Our findings pave the way for future research and potential therapeutic strategies.
{"title":"Impairment of hippocampal gamma oscillations, mitochondria and neurovascular function in CADASIL","authors":"Wenchao Shao, Daniel V Oliveira, Luana Naia, Yue Li, Katrine Dahl Bjørnholm, Arturo G Isla, Per Uhlén, Raj Kalaria, Saskia A J Lesnik Oberstein, Urban Lendahl, Luis EnriqueArroyo-García, ShaoBo Jin, Helena Karlström","doi":"10.1093/brain/awag033","DOIUrl":"https://doi.org/10.1093/brain/awag033","url":null,"abstract":"Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a small vessel disease caused by cysteine-altering NOTCH3 gene variants, leading to vascular smooth muscle cell degeneration, compromised cerebral blood flow, subcortical ischemic infarcts, cognitive decline, and often ultimately vascular dementia. Little is known about the cellular and molecular effects downstream of the cerebral ischemia in CADASIL, or whether brain regions known to be involved in dementia, such as the hippocampus, are particularly susceptible to such pathological downstream changes. In this study, we used a humanized CADASIL mouse model harbouring the p.(Arg182Cys) variant (R182C-TgN3), post-mortem human CADASIL brain sections with four different NOTCH3 gene variants and primary human cerebral vascular smooth muscle cells (VSMCs) harbouring the p.R133C NOTCH3 variant as primary cellular models to characterise the properties and contribution of mutant VSMCs to cognitive impairment. To specifically evaluate neuronal, mitochondrial and neurovascular function, we performed ex vivo electrophysiology, immunohistochemistry (confocal and iDISCO+ methods), western blotting, Seahorse assay, quantitative polymerase chain reaction (qPCR), and single-cell RNA sequencing. In the CADASIL mice, hippocampal gamma oscillation patterns were impaired along with significant decreases in neuronal fiber length and aberrant neuronal morphology. The latter two phenotypes were also observed in post-mortem brain tissue from CADASIL patients. Consistent with these findings, we noted significantly lower levels of mitochondrial respiratory complexes in the CADASIL mouse hippocampus, isolated mouse brain vessels and primary human cerebral VSMCs. The human cerebral VSMCs exhibited reduced oxygen consumption rates leading to reduced ATP production as well as decreased glycolytic capacity in conjunction with increased pro-inflammatory gene expression, suggesting a broader impact on cellular energy metabolism and a neuroinflammatory process. In the CADASIL mice, we also observed extensive accumulation of the NOTCH3 extracellular domain in hippocampal vessels. Light sheet imaging with iDISCO+ clearing demonstrated substantial VSMC loss and reduced vessel density in the hippocampus at 9 months of age. Additionally, 3D imaging showed increased microglial attachment to vessels and enlargement of the size of the vessel-associated microglia in CADASIL mice. Single-cell RNA sequencing revealed a microglial subcluster expressing genes involved in mitochondrial respiration and inflammation. Collectively, our results reveal how small vessel pathology in CADASIL leads to significant neuronal pathology in the hippocampus involving metabolic and neuroinflammatory changes and highlight the critical role of the neurovascular unit. Our findings pave the way for future research and potential therapeutic strategies.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"17 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098262","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}
Ruth B De-Paula, Jonggeol Kim, Herve Rhinn, Hiba Saade, Fatima Chavez, Téah Segura, Maria Valeria Lozano, Michelle Etoundi, Karla Silos, Naomi Kass, Viktoriya Korchina, Harshavardhan Doddapaneni, Eric Venner, Joseph C Masdeu, Valory Pavlik, Melissa M Yu, Chi-Ying R Lin, Joseph Jankovic, Aron S Buchman, Donna Muzny, Richard A Gibbs, Sarah H Elsea, Asa Abeliovich, Peter Lansbury, Nora Vanegas-Arroyave, Chad A Shaw, Joshua M Shulman
The molecular pathways linking genetic variants to Parkinson’s disease (PD) onset and progression remain incompletely defined; however, risk alleles in multiple genes, including GBA1, strongly implicate lipid metabolism. To systematically identify causal biomarker signatures, we analyzed comprehensive metabolome profiles from blood plasma in 149 PD patients and 150 controls, along with complementary genetic, RNA-sequencing, and metabolic data from other available clinical and pathologic cohorts. Using colocalization and summary-data-based Mendelian randomization, we tested whether expression and metabolic quantitative trait loci mediate the association between implicated genetic variants and PD risk. We further integrated differential metabolomics and proteomics from blood and brain to reveal pertinent mechanisms. We show that common PD risk variants at the serine palmitoyltransferase small subunit B (SPTSSB) locus, a key regulator of de novo sphingolipid biosynthesis, are associated with increased SPTSSB brain expression and elevated plasma ceramides. Additional analyses strongly support our hypothesis that a common SPTSSB causal variant is responsible for PD risk as well as the expression and metabolic quantitative trait loci. Multiple sphingolipids and fatty acid derivatives were perturbed in PD, and we identified both unique and shared features with the Alzheimer’s disease metabolome. A PD acylcarnitine signature was further replicated in human postmortem brain tissue, when comparing those with or without preclinical Lewy body pathology. Integrated analysis of complementary brain proteomic profiles revealed dysregulation of mitochondrial processes dependent on acylcarnitines, including fatty acid beta-oxidation, the tricarboxylic acid cycle, and oxidative phosphorylation. Our results identify promising biomarkers and reveal a causal chain linking genetic variation to altered gene/protein expression, lipid dysmetabolism, and the manifestation of PD.
{"title":"Mapping the causal chain from genetic risk variants to lipid dysmetabolism in Parkinson’s disease","authors":"Ruth B De-Paula, Jonggeol Kim, Herve Rhinn, Hiba Saade, Fatima Chavez, Téah Segura, Maria Valeria Lozano, Michelle Etoundi, Karla Silos, Naomi Kass, Viktoriya Korchina, Harshavardhan Doddapaneni, Eric Venner, Joseph C Masdeu, Valory Pavlik, Melissa M Yu, Chi-Ying R Lin, Joseph Jankovic, Aron S Buchman, Donna Muzny, Richard A Gibbs, Sarah H Elsea, Asa Abeliovich, Peter Lansbury, Nora Vanegas-Arroyave, Chad A Shaw, Joshua M Shulman","doi":"10.1093/brain/awag039","DOIUrl":"https://doi.org/10.1093/brain/awag039","url":null,"abstract":"The molecular pathways linking genetic variants to Parkinson’s disease (PD) onset and progression remain incompletely defined; however, risk alleles in multiple genes, including GBA1, strongly implicate lipid metabolism. To systematically identify causal biomarker signatures, we analyzed comprehensive metabolome profiles from blood plasma in 149 PD patients and 150 controls, along with complementary genetic, RNA-sequencing, and metabolic data from other available clinical and pathologic cohorts. Using colocalization and summary-data-based Mendelian randomization, we tested whether expression and metabolic quantitative trait loci mediate the association between implicated genetic variants and PD risk. We further integrated differential metabolomics and proteomics from blood and brain to reveal pertinent mechanisms. We show that common PD risk variants at the serine palmitoyltransferase small subunit B (SPTSSB) locus, a key regulator of de novo sphingolipid biosynthesis, are associated with increased SPTSSB brain expression and elevated plasma ceramides. Additional analyses strongly support our hypothesis that a common SPTSSB causal variant is responsible for PD risk as well as the expression and metabolic quantitative trait loci. Multiple sphingolipids and fatty acid derivatives were perturbed in PD, and we identified both unique and shared features with the Alzheimer’s disease metabolome. A PD acylcarnitine signature was further replicated in human postmortem brain tissue, when comparing those with or without preclinical Lewy body pathology. Integrated analysis of complementary brain proteomic profiles revealed dysregulation of mitochondrial processes dependent on acylcarnitines, including fatty acid beta-oxidation, the tricarboxylic acid cycle, and oxidative phosphorylation. Our results identify promising biomarkers and reveal a causal chain linking genetic variation to altered gene/protein expression, lipid dysmetabolism, and the manifestation of PD.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"79 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146101324","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}
Ammar T Abdulaziz,Jinmei Li,Josemir W Sander,Dong Zhou
{"title":"Reply: The neurological significance of folate deficiency in women with epilepsy.","authors":"Ammar T Abdulaziz,Jinmei Li,Josemir W Sander,Dong Zhou","doi":"10.1093/brain/awag027","DOIUrl":"https://doi.org/10.1093/brain/awag027","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":"281 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073094","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}
Creative thinking is a fundamental aspect of human cognition, enabling the production of novel and useful ideas. It is hypothesized to emerge from the binding and reconfiguration of existing knowledge, through the generation of remote semantic associations and their combination in original and meaningful ways, respectively supported by the default mode (DMN) and executive control (ECN) networks. At the crossroads of these two networks, the rostral prefrontal cortex (PFC) is proposed as a key hub for DMN-ECN interactions, possibly supporting the interplay between generative and combinatory creative processes. However, the specific contributions of its medial and lateral subdivisions to creativity remain unclear. In this study, we aimed to characterize the involvement of the rostral PFC in creative cognition through the lens of behavioural variant frontotemporal dementia (bvFTD), a relevant pathological model as it primarily affects the rostral PFC and alters intrinsic connectivity within the DMN and ECN. Using whole-brain voxel-based morphometry, we explored the brain regions critical for the generation and combination of remote semantic associates, respectively, but also for creative abilities, thought to involve both types of processes. Using resting state functional connectivity and gradient mapping techniques, we also explored functional connectivity profiles within the rostral PFC and how connectivity variations within this region predict creative performance. As a result, we found a critical role of the rostromedial PFC for generating remote semantic associations and of the rostrolateral PFC for combining semantic associates, while both regions were critical for creative abilities. Moreover, we showed that intrinsic connectivity of rostral PFC is organized along a mediolateral functional gradient, segregating the rostromedial PFC, connected to the DMN, and the rostrolateral PFC, connected to the ECN. Finally, we showed that the range of this functional gradient, representing the functional differentiation between the ECN and DMN, predicts creative abilities. Overall, this study advances our understanding of creative cognition, its relationships to the anatomical and functional organization of the prefrontal cortex, and its impairment in bvFTD.
{"title":"A rostral prefrontal mediolateral gradient predicts creativity in frontotemporal dementia.","authors":"Victor Altmayer,Marcela Ovando-Tellez,Théophile Bieth,Bénédicte Batrancourt,Armelle Rametti-Lacroux,Sarah Moreno-Rodriguez,Arabella Bouzigues,Vincent Ledu,Béatrice Garcin,Alizée Lopez-Persem,Daniel Margulies,Richard Levy,Emmanuelle Volle, ","doi":"10.1093/brain/awag032","DOIUrl":"https://doi.org/10.1093/brain/awag032","url":null,"abstract":"Creative thinking is a fundamental aspect of human cognition, enabling the production of novel and useful ideas. It is hypothesized to emerge from the binding and reconfiguration of existing knowledge, through the generation of remote semantic associations and their combination in original and meaningful ways, respectively supported by the default mode (DMN) and executive control (ECN) networks. At the crossroads of these two networks, the rostral prefrontal cortex (PFC) is proposed as a key hub for DMN-ECN interactions, possibly supporting the interplay between generative and combinatory creative processes. However, the specific contributions of its medial and lateral subdivisions to creativity remain unclear. In this study, we aimed to characterize the involvement of the rostral PFC in creative cognition through the lens of behavioural variant frontotemporal dementia (bvFTD), a relevant pathological model as it primarily affects the rostral PFC and alters intrinsic connectivity within the DMN and ECN. Using whole-brain voxel-based morphometry, we explored the brain regions critical for the generation and combination of remote semantic associates, respectively, but also for creative abilities, thought to involve both types of processes. Using resting state functional connectivity and gradient mapping techniques, we also explored functional connectivity profiles within the rostral PFC and how connectivity variations within this region predict creative performance. As a result, we found a critical role of the rostromedial PFC for generating remote semantic associations and of the rostrolateral PFC for combining semantic associates, while both regions were critical for creative abilities. Moreover, we showed that intrinsic connectivity of rostral PFC is organized along a mediolateral functional gradient, segregating the rostromedial PFC, connected to the DMN, and the rostrolateral PFC, connected to the ECN. Finally, we showed that the range of this functional gradient, representing the functional differentiation between the ECN and DMN, predicts creative abilities. Overall, this study advances our understanding of creative cognition, its relationships to the anatomical and functional organization of the prefrontal cortex, and its impairment in bvFTD.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"74 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073095","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}
Youngshin Lim, Shyam K Akula, Abigail K Myers, Connie Chen, Katherine A Rafael, Michaela G Ibach, Edwin Trevathan, Christopher A Walsh, Jeffrey A Golden, Ginam Cho
Cortical interneuron (cIN) dysfunction is associated with various neurodevelopmental and neurological disorders, including developmental epilepsies, autism spectrum disorders, and intellectual disabilities. Mutations in ARX (aristaless-related homeobox) are linked to these conditions, with or without accompanying structural brain anomalies. We have previously demonstrated that the loss of Arx in the mouse ganglionic eminence, the birthplace of cINs, is associated with seizures in mice, whereas the loss in cortical excitatory neuron progenitor cells results in structural anomalies but no seizures. To elucidate the pathophysiological role of ARX in cINs and their relationship to the seizure phenotype, Arx conditional mutant mouse lines were interrogated using Gad2- and Nkx2.1-Cre drivers to target distinct populations in the cIN lineage. Our data demonstrate that the abrogation of ARX results in cIN density and distribution defects as well as perinatal lethality. In these mice, we observed defects in cell cycle exit, a biased loss of the marginal zone migration stream of cINs, shifts in cell fate from caudal ganglionic eminence (CGE) to medial ganglionic eminence (MGE) identity, and a reduced number of parvalbumin⁺ and somatostatin⁺ cINs, with parvalbumin⁺ cINs being more severely affected. Single-cell RNA sequencing combined with chromatin immunoprecipitation (ChIP)-seq revealed ARX regulates key processes involved in cell cycle progression, cIN subtype differentiation, guidance cues and receptors, as well as other transcription factors. Interrogation of one downregulated target gene, Lmo1, uncovered a potential mechanism by which ARX regulates cIN number and distribution in the cortex. Cortical slice cultures demonstrate that LMO1 inhibits cIN migration by repressing Cxcr4 expression, which encodes a key receptor involved in cortical guidance. These data indicate ARX positively regulates cIN migration by derepressing LMO1’s repressive role. Consistent with our mouse model, we observed a significant loss of parvalbumin+ and somatostatin+ cINs in the brain of a patient carrying a pathogenic variant of ARX and diagnosed with developmental epileptic encephalopathy. Together our data provide novel insights into how ARX and its target genes regulate cIN development and migration and the pathogenic mechanisms of a spectrum of neurodevelopmental disorders linked to loss of ARX.
{"title":"ARX mutation-associated interneuron defects provide insights into mechanisms underlying developmental epilepsies","authors":"Youngshin Lim, Shyam K Akula, Abigail K Myers, Connie Chen, Katherine A Rafael, Michaela G Ibach, Edwin Trevathan, Christopher A Walsh, Jeffrey A Golden, Ginam Cho","doi":"10.1093/brain/awag036","DOIUrl":"https://doi.org/10.1093/brain/awag036","url":null,"abstract":"Cortical interneuron (cIN) dysfunction is associated with various neurodevelopmental and neurological disorders, including developmental epilepsies, autism spectrum disorders, and intellectual disabilities. Mutations in ARX (aristaless-related homeobox) are linked to these conditions, with or without accompanying structural brain anomalies. We have previously demonstrated that the loss of Arx in the mouse ganglionic eminence, the birthplace of cINs, is associated with seizures in mice, whereas the loss in cortical excitatory neuron progenitor cells results in structural anomalies but no seizures. To elucidate the pathophysiological role of ARX in cINs and their relationship to the seizure phenotype, Arx conditional mutant mouse lines were interrogated using Gad2- and Nkx2.1-Cre drivers to target distinct populations in the cIN lineage. Our data demonstrate that the abrogation of ARX results in cIN density and distribution defects as well as perinatal lethality. In these mice, we observed defects in cell cycle exit, a biased loss of the marginal zone migration stream of cINs, shifts in cell fate from caudal ganglionic eminence (CGE) to medial ganglionic eminence (MGE) identity, and a reduced number of parvalbumin⁺ and somatostatin⁺ cINs, with parvalbumin⁺ cINs being more severely affected. Single-cell RNA sequencing combined with chromatin immunoprecipitation (ChIP)-seq revealed ARX regulates key processes involved in cell cycle progression, cIN subtype differentiation, guidance cues and receptors, as well as other transcription factors. Interrogation of one downregulated target gene, Lmo1, uncovered a potential mechanism by which ARX regulates cIN number and distribution in the cortex. Cortical slice cultures demonstrate that LMO1 inhibits cIN migration by repressing Cxcr4 expression, which encodes a key receptor involved in cortical guidance. These data indicate ARX positively regulates cIN migration by derepressing LMO1’s repressive role. Consistent with our mouse model, we observed a significant loss of parvalbumin+ and somatostatin+ cINs in the brain of a patient carrying a pathogenic variant of ARX and diagnosed with developmental epileptic encephalopathy. Together our data provide novel insights into how ARX and its target genes regulate cIN development and migration and the pathogenic mechanisms of a spectrum of neurodevelopmental disorders linked to loss of ARX.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"38 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146101453","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}
Francisco Cardoso, Débora Maia, Ricardo Maciel, Jonathan Carr, Taku Hatano, Alexandra Durr, Werner Poewe
Huntington disease (HD) phenocopies are conditions characterized by a phenotype similar to HD but without a pathogenic repeat expansion in the HTT gene. The percentage of patients who have an HD phenotype but subsequently are shown not to carry a repeat expansion ranges from 2% to 40%, depending on the ethnicity and the geographic location of the population studied, as well as the resources available for investigation of the underlying causes. In descending order of frequency, genetic causes are Huntington Disease-like 2/JHP3, spinocerebellar ataxia genes (SCA17/TBP, SCA12/PPP2R2B and SCA3/ATXN3, CACNA1A), and frontotemporal dementia genes (C9orf72, and VCP). In addition, it has been established that a growing list of acquired causes may also mimic HD, including autoimmune illnesses such as primary antiphospholipid syndrome, paraneoplastic chorea, and anti-IGLON5. Here we aim to review the epidemiology, aetiology, clinical and laboratory findings of the wide range of conditions associated with HD phenocopies, and proceed to suggest a practical diagnostic approach to the investigation of HD phenocopies taking into account the age at onset, ethnicity, and geographic location of individuals.
{"title":"Non-Huntington’s disease chorea: an expanding universe with acquired causes","authors":"Francisco Cardoso, Débora Maia, Ricardo Maciel, Jonathan Carr, Taku Hatano, Alexandra Durr, Werner Poewe","doi":"10.1093/brain/awag038","DOIUrl":"https://doi.org/10.1093/brain/awag038","url":null,"abstract":"Huntington disease (HD) phenocopies are conditions characterized by a phenotype similar to HD but without a pathogenic repeat expansion in the HTT gene. The percentage of patients who have an HD phenotype but subsequently are shown not to carry a repeat expansion ranges from 2% to 40%, depending on the ethnicity and the geographic location of the population studied, as well as the resources available for investigation of the underlying causes. In descending order of frequency, genetic causes are Huntington Disease-like 2/JHP3, spinocerebellar ataxia genes (SCA17/TBP, SCA12/PPP2R2B and SCA3/ATXN3, CACNA1A), and frontotemporal dementia genes (C9orf72, and VCP). In addition, it has been established that a growing list of acquired causes may also mimic HD, including autoimmune illnesses such as primary antiphospholipid syndrome, paraneoplastic chorea, and anti-IGLON5. Here we aim to review the epidemiology, aetiology, clinical and laboratory findings of the wide range of conditions associated with HD phenocopies, and proceed to suggest a practical diagnostic approach to the investigation of HD phenocopies taking into account the age at onset, ethnicity, and geographic location of individuals.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"7 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146071653","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}
This scientific commentary refers to ‘Treatment evolution in spinal muscular atrophy: insights from the SMArtCARE registry’ by Voigt-Müller et al. (https://doi.org/10.1093/brain/awaf472).
这篇科学评论引用了voigt - m ller等人的“脊髓性肌萎缩症的治疗演变：来自SMArtCARE注册的见解”（https://doi.org/10.1093/brain/awaf472）。
{"title":"Real-world treatment dynamics in spinal muscular atrophy: what the SMArtCARE registry renders visible","authors":"Kentaro Okamoto","doi":"10.1093/brain/awag041","DOIUrl":"https://doi.org/10.1093/brain/awag041","url":null,"abstract":"This scientific commentary refers to ‘Treatment evolution in spinal muscular atrophy: insights from the SMArtCARE registry’ by Voigt-Müller et al. (https://doi.org/10.1093/brain/awaf472).","PeriodicalId":9063,"journal":{"name":"Brain","volume":"73 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146071654","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}
Aikaterini Smaragdi Papadopoulou, Christian Landles, Edward J Smith, Marie K Bondulich, Annett Boeddrich, Maria Canibano-Pico, Emily C E Danby, Franziska Hoschek, Arzo Iqbal, Samuel T Jones, Nancy Neuendorf, Iulia M Nita, Georgina F Osborne, Jemima Phillips, Maximilian Wagner, Erich E Wanker, Jonathan R Greene, Andreas Neueder, Gillian P Bates
The mutation that causes Huntington’s disease is a CAG repeat expansion in exon 1 of the huntingtin gene (HTT) that leads to an abnormally long polyglutamine tract in the huntingtin protein (HTT). Mutant CAG repeats are unstable and increase in size in specific neurons and brain regions with age, a phenomenon that constitutes the first step in the pathogenesis of the disease. In the presence of an expanded CAG repeat, cryptic polyA sites in intron 1 of the HTT pre-mRNA can become activated leading to the polyadenylation of a prematurely terminated transcript, HTT1a. This encodes the HTT1a protein, which is known to be very aggregation-prone and highly pathogenic. Given that the longer the CAG repeat the more HTT1a is generated, could the production of HTT1a be the mechanism through which somatic CAG repeat expansion exerts its pathogenic consequences? Resolving this issue is very important for the design of therapeutic approaches to lower huntingtin levels. We have used a CRISPR-Cas9 approach to prevent the production of HTT1a in a knock-in mouse model of Huntington’s disease. All potential cryptic polyA sites were deleted from Htt intron 1 in HdhQ150 mice and colonies were established that were heterozygous for the intron 1 deletion on a mutant allele (HdhQ150ΔI) and heterozygous for the deletion on a wild-type allele (WTΔI). The CAG repeat sizes in the HdhQ150 and HdhQ150ΔI colonies were well-matched at approximately 195 CAGs. As predicted, the deletion of the cryptic polyA sites from Htt intron 1 prevented the generation of the Htt1a transcript in the HdhQ150ΔI mice. However, very low levels of the HTT1a protein were detected, which resulted from a Htt readthrough product of exon 1 and exon 2, that had retained the deleted intron and terminated at a cryptic polyA site in intron 2. HdhQ150, HdhQ150ΔI, wild-type and WTΔI mice were studied until 17 months of age. Immunohistochemical and homogeneous time resolved fluorescence analysis showed that HTT aggregation in both HdhQ150 and HdhQ150ΔI brains contained HTT1a, but the dramatic decrease in soluble HTT1a levels in HdhQ150ΔI brains delayed the appearance of aggregated HTT1a by several months. Although this delay in aggregate pathology only partially reversed transcriptional dysregulation, the biomarkers NEFL and BRP39 (YKL40) remained at wild-type levels in HdhQ150ΔI mice at 17 months of age. These data demonstrate that the production of HTT1a initiates HTT aggregation and that it is important to target HTT1a in huntingtin-lowering therapeutic strategies.
{"title":"The HTT1a protein initiates HTT aggregation in a knock-in mouse model of Huntington’s disease","authors":"Aikaterini Smaragdi Papadopoulou, Christian Landles, Edward J Smith, Marie K Bondulich, Annett Boeddrich, Maria Canibano-Pico, Emily C E Danby, Franziska Hoschek, Arzo Iqbal, Samuel T Jones, Nancy Neuendorf, Iulia M Nita, Georgina F Osborne, Jemima Phillips, Maximilian Wagner, Erich E Wanker, Jonathan R Greene, Andreas Neueder, Gillian P Bates","doi":"10.1093/brain/awag040","DOIUrl":"https://doi.org/10.1093/brain/awag040","url":null,"abstract":"The mutation that causes Huntington’s disease is a CAG repeat expansion in exon 1 of the huntingtin gene (HTT) that leads to an abnormally long polyglutamine tract in the huntingtin protein (HTT). Mutant CAG repeats are unstable and increase in size in specific neurons and brain regions with age, a phenomenon that constitutes the first step in the pathogenesis of the disease. In the presence of an expanded CAG repeat, cryptic polyA sites in intron 1 of the HTT pre-mRNA can become activated leading to the polyadenylation of a prematurely terminated transcript, HTT1a. This encodes the HTT1a protein, which is known to be very aggregation-prone and highly pathogenic. Given that the longer the CAG repeat the more HTT1a is generated, could the production of HTT1a be the mechanism through which somatic CAG repeat expansion exerts its pathogenic consequences? Resolving this issue is very important for the design of therapeutic approaches to lower huntingtin levels. We have used a CRISPR-Cas9 approach to prevent the production of HTT1a in a knock-in mouse model of Huntington’s disease. All potential cryptic polyA sites were deleted from Htt intron 1 in HdhQ150 mice and colonies were established that were heterozygous for the intron 1 deletion on a mutant allele (HdhQ150ΔI) and heterozygous for the deletion on a wild-type allele (WTΔI). The CAG repeat sizes in the HdhQ150 and HdhQ150ΔI colonies were well-matched at approximately 195 CAGs. As predicted, the deletion of the cryptic polyA sites from Htt intron 1 prevented the generation of the Htt1a transcript in the HdhQ150ΔI mice. However, very low levels of the HTT1a protein were detected, which resulted from a Htt readthrough product of exon 1 and exon 2, that had retained the deleted intron and terminated at a cryptic polyA site in intron 2. HdhQ150, HdhQ150ΔI, wild-type and WTΔI mice were studied until 17 months of age. Immunohistochemical and homogeneous time resolved fluorescence analysis showed that HTT aggregation in both HdhQ150 and HdhQ150ΔI brains contained HTT1a, but the dramatic decrease in soluble HTT1a levels in HdhQ150ΔI brains delayed the appearance of aggregated HTT1a by several months. Although this delay in aggregate pathology only partially reversed transcriptional dysregulation, the biomarkers NEFL and BRP39 (YKL40) remained at wild-type levels in HdhQ150ΔI mice at 17 months of age. These data demonstrate that the production of HTT1a initiates HTT aggregation and that it is important to target HTT1a in huntingtin-lowering therapeutic strategies.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"23 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098263","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}
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