Absence of subcerebral projection neurons delays disease onset and extends survival in a mouse model of ALS
Absence of subcerebral projection neurons delays disease onset and extends survival in a mouse model of ALS
Abstract Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease of adulthood that affects voluntary motricity and rapidly leads to full paralysis and death. ALS arises from the combined degeneration of motoneurons in the spinal cord and brain stem, responsible for muscle denervation, and corticospinal projection neurons (CSN), responsible for emergence of the upper motor neuron syndrome. Recent studies carried on ALS patients suggest that the disease may initiate in the motor cortex and spread to its projection targets. However, this “corticofugal hypothesis” of ALS has not yet been specifically challenged. Here, we provide a direct test of this hypothesis by genetically removing subcerebral projection neurons (SubCerPN), including CSN, in Sod1G86R mice, a mouse model of ALS. Ablation of the transcription factor Fezf2, leading to the complete absence of all SubCerPN, delays disease onset, reduces weight loss and motor impairment, and increases survival without modifying disease duration. Importantly absence of SubCerPN and CSN also limits pre-symptomatic hyperreflexia. Together, our results demonstrate that major corticofugal tracts are critical to ALS onset, and that SubCerPN and CSN in particular may carry detrimental signals to their downstream targets. In its whole, this study provides first experimental arguments in favour of the corticofugal hypothesis of ALS.
Rouaux Caroline、Bichara Charlotte、Scekic-Zahirovic Jelena、Fischer Mathieu、Burg Thibaut、Lefebvre Fran?ois、Cordero-Erausquin Matilde、Stuart-Lopez Geoffrey
Inserm UMR_S 1118, M¨|canismes centraux et p¨|riph¨|riques de la neurod¨|g¨|n¨|rescence, Facult¨| de M¨|decine, Universit¨| de StrasbourgUPR 3212, Institut des neurosciences cellulaires et int¨|gratives, UPR 3212 CNRS, Universit¨| de StrasbourgInserm UMR_S 1118, M¨|canismes centraux et p¨|riph¨|riques de la neurod¨|g¨|n¨|rescence, Facult¨| de M¨|decine, Universit¨| de StrasbourgInserm UMR_S 1118, M¨|canismes centraux et p¨|riph¨|riques de la neurod¨|g¨|n¨|rescence, Facult¨| de M¨|decine, Universit¨| de Strasbourg||Department of Paediatrics, John Radcliffe Hospital, University of OxfordInserm UMR_S 1118, M¨|canismes centraux et p¨|riph¨|riques de la neurod¨|g¨|n¨|rescence, Facult¨| de M¨|decine, Universit¨| de StrasbourgGMRC, service de sant¨| publique, H?pitaux Universitaires de StrasbourgUPR 3212, Institut des neurosciences cellulaires et int¨|gratives, UPR 3212 CNRS, Universit¨| de StrasbourgInserm UMR_S 1118, M¨|canismes centraux et p¨|riph¨|riques de la neurod¨|g¨|n¨|rescence, Facult¨| de M¨|decine, Universit¨| de Strasbourg
神经病学、精神病学基础医学生物科学研究方法、生物科学研究技术
Amyotrophic lateral sclerosiscorticospinal neuronscerebral cortexSod1G86Rcorticofugal hypothesis
Rouaux Caroline,Bichara Charlotte,Scekic-Zahirovic Jelena,Fischer Mathieu,Burg Thibaut,Lefebvre Fran?ois,Cordero-Erausquin Matilde,Stuart-Lopez Geoffrey.Absence of subcerebral projection neurons delays disease onset and extends survival in a mouse model of ALS[EB/OL].(2025-03-28)[2025-05-01].https://www.biorxiv.org/content/10.1101/849935.点此复制
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