Differential neuronal vulnerability to C9orf72 repeat expansion driven by Xbp1-induced endoplasmic reticulum-associated degradation

Neurodegenerative diseases are characterized by the localized loss of neurons. Why cell death is triggered only in specific neuronal populations and whether it is the response to toxic insults or the initial cellular state that determines their vulnerability is unknown. To understand individual cell...

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Detalles Bibliográficos
Autores: Shen, Dunxin, Vincent, Alec, Udine, Evan, Buhidma, Yazead, Anoar, Sharifah, Tsintzas, Elli, Maeland, Marie, Xu, Dongwei, Carcolé, Mireia, Osumi-Sutherland, David, Aleyakpo, Benjamin, Hull, Alexander, Martínez Corrales, Guillermo, Woodling, Nathan, Rademakers, Rosa, Isaacs, Adrian M, Frigerio, Carlo, van Blitterswijk, Marka, Lashley, Tammaryn, Niccoli, Teresa
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:dnet:digitalcsic_::a2f24e774845537275d75d33fb8ba848
Acceso en línea:http://hdl.handle.net/10261/431597
https://api.elsevier.com/content/abstract/scopus_id/105002144381
Access Level:acceso abierto
Palabra clave:C9orf72
ALS
FTD
Xbp1
Unfolded protein response
Neuronal vulnerability
ERAD
Drosophilaprotein homeostasis
C9
Descripción
Sumario:Neurodegenerative diseases are characterized by the localized loss of neurons. Why cell death is triggered only in specific neuronal populations and whether it is the response to toxic insults or the initial cellular state that determines their vulnerability is unknown. To understand individual cell responses to disease, we profiled their transcriptional signatures throughout disease development in a Drosophila model of C9orf72 (G4C2) repeat expansion (C9), the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis. We identified neuronal populations specifically vulnerable or resistant to C9 expression and found an upregulation of protein homeostasis pathways in resistant neurons at baseline. Overexpression of Xbp1s, a key regulator of the unfolded protein response and a central node in the resistance network, rescues C9 toxicity. This study shows that neuronal vulnerability depends on the intrinsic transcriptional state of neurons and that leveraging resistant neurons’ properties can boost resistance in vulnerable neurons.

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