E. Genin, S. Bannwarth, Baptiste Ropert, F. Lespinasse, Alessandra Mauri-Crouzet, Gaëlle Augé, K. Fragaki, Charlotte Cochaud, E. Donnarumma, S. Lacas‐Gervais, T. Wai, V. Paquis-Flucklinger
CHCHD10 is an amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) gene that encodes a mitochondrial protein whose precise function is unclear. Here we show that CHCHD10 interacts with the Stomatin-Like Protein 2 (SLP2) and participates to the stability of the Prohibitin (PHB) complex in the inner mitochondrial membrane. By using patient fibroblasts and mouse models expressing the same CHCHD10 variant (p.Ser59Leu), we show that SLP2 forms aggregates with prohibitins, found in vivo in the hippocampus and as aggresome-like inclusions in spinal motor neurons of Chchd10S59L/+ mice. Affected cells and tissues display instability of the PHB complex which participates at least in part to the activation of the OMA1 cascade with OPA1 processing leading to mitochondrial fragmentation, abnormal mitochondrial cristae morphogenesis and neuronal death found in spinal cord and the hippocampus of Chchd10S59L/+ animals. Destabilization of the PHB complex leads to the instability of the mitochondrial contact site and cristae organizing system (MICOS) complex, likely via the disruption of OPA1/Mitofilin interaction. Thus, SLP2/PHB aggregates and destabilization of the PHB complex are critical in the sequence of events leading to motor neuron death in CHCHD10S59L-related disease.
CHCHD10是一种肌萎缩性侧索硬化症/额颞叶痴呆(ALS/FTD)基因，其编码的线粒体蛋白的确切功能尚不清楚。在这里，我们发现CHCHD10与Stomatin-Like Protein 2 (SLP2)相互作用，并参与线粒体内膜中prohibition - tin (PHB)复合物的稳定性。通过使用表达相同CHCHD10变体(p.Ser59Leu)的患者成纤维细胞和小鼠模型，我们发现SLP2与禁止蛋白形成聚集体，在体内的海马中发现，并在Chchd10S59L/+小鼠的脊髓运动神经元中发现聚集体样包裹体。受影响的细胞和组织表现出PHB复合物的不稳定性，这至少部分参与了OMA1级联与OPA1加工的激活，导致在Chchd10S59L/+动物的脊髓和海马中发现的线粒体断裂、线粒体嵴形态发生异常和神经元死亡。PHB复合物的不稳定导致线粒体接触位点和嵴组织系统(MICOS)复合物的不稳定，可能是通过破坏OPA1/Mitofilin相互作用。因此，SLP2/PHB聚集和PHB复合物的不稳定是导致chchd10s59l相关疾病中运动神经元死亡的一系列事件的关键。
{"title":"CHCHD10 and SLP2 control the stability of the PHB complex: a key factor for motor neuron viability.","authors":"E. Genin, S. Bannwarth, Baptiste Ropert, F. Lespinasse, Alessandra Mauri-Crouzet, Gaëlle Augé, K. Fragaki, Charlotte Cochaud, E. Donnarumma, S. Lacas‐Gervais, T. Wai, V. Paquis-Flucklinger","doi":"10.1093/brain/awac197","DOIUrl":"https://doi.org/10.1093/brain/awac197","url":null,"abstract":"CHCHD10 is an amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) gene that encodes a mitochondrial protein whose precise function is unclear. Here we show that CHCHD10 interacts with the Stomatin-Like Protein 2 (SLP2) and participates to the stability of the Prohibitin (PHB) complex in the inner mitochondrial membrane. By using patient fibroblasts and mouse models expressing the same CHCHD10 variant (p.Ser59Leu), we show that SLP2 forms aggregates with prohibitins, found in vivo in the hippocampus and as aggresome-like inclusions in spinal motor neurons of Chchd10S59L/+ mice. Affected cells and tissues display instability of the PHB complex which participates at least in part to the activation of the OMA1 cascade with OPA1 processing leading to mitochondrial fragmentation, abnormal mitochondrial cristae morphogenesis and neuronal death found in spinal cord and the hippocampus of Chchd10S59L/+ animals. Destabilization of the PHB complex leads to the instability of the mitochondrial contact site and cristae organizing system (MICOS) complex, likely via the disruption of OPA1/Mitofilin interaction. Thus, SLP2/PHB aggregates and destabilization of the PHB complex are critical in the sequence of events leading to motor neuron death in CHCHD10S59L-related disease.","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"2 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"128230447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Progress towards predicting neurodegeneration and dementia after traumatic brain injury.","authors":"Neil S N Graham","doi":"10.1093/brain/awac179","DOIUrl":"https://doi.org/10.1093/brain/awac179","url":null,"abstract":"","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"114136460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Arcuate fasciculus' middle and ventral temporal connections undercut by tract-tracing evidence.","authors":"Y. Becker, K. Loh, O. Coulon, A. Meguerditchian","doi":"10.1093/brain/awac200","DOIUrl":"https://doi.org/10.1093/brain/awac200","url":null,"abstract":"","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"121108480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Homeostatic feelings and the biology of consciousness.","authors":"António Sérgio Damásio, H. Damasio","doi":"10.1093/brain/awac194","DOIUrl":"https://doi.org/10.1093/brain/awac194","url":null,"abstract":"","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"26 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"117204530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Reply: Arcuate fasciculus' middle and ventral temporal connections undercut by tract-tracing evidence.","authors":"D. Giampiccolo, H. Duffau","doi":"10.1093/brain/awac201","DOIUrl":"https://doi.org/10.1093/brain/awac201","url":null,"abstract":"","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"78 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"123465744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Catatonia: looking back and moving forward.","authors":"D. Hirjak, R. Wolf, G. Landwehrmeyer, G. Northoff","doi":"10.1093/brain/awac196","DOIUrl":"https://doi.org/10.1093/brain/awac196","url":null,"abstract":"","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"29 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"131937345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Early bioenergetic and autophagy impairments at the Parkinson's disease synapse.","authors":"G. A. Prieto, C. Cotman","doi":"10.1093/brain/awac191","DOIUrl":"https://doi.org/10.1093/brain/awac191","url":null,"abstract":"","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"127002140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"What plasma biomarkers tell us about hippocampal microstructural changes in Alzheimer's disease.","authors":"S. Toniolo","doi":"10.1093/brain/awac190","DOIUrl":"https://doi.org/10.1093/brain/awac190","url":null,"abstract":"","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"5 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"133615009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"On St Teresa of Avila's mysticism: epilepsy and/or ecstasy?","authors":"G. Huberfeld, J. Pallud, E. Drouin, P. Hautecoeur","doi":"10.1093/brain/awac183","DOIUrl":"https://doi.org/10.1093/brain/awac183","url":null,"abstract":"","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"24 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"127172103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Correction to: Brain amyloid-β oligomers in ageing and Alzheimer's disease.","authors":"","doi":"10.1093/brain/awac143","DOIUrl":"https://doi.org/10.1093/brain/awac143","url":null,"abstract":"","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"19 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"127983610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","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：