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

• DOI: 10.1016/j.celrep.2025.115459
• Publication Date: 2025-04-08T21:42:13Z
• Authors: Dunxin Shen; Alec Vincent; Evan Udine; Yazead Buhidma; Sharifah Anoar; Elli Tsintzas; Marie Maeland; Dongwei Xu; Mireia Carcolé; David Osumi-Suthe...; Benjamin Aleyakpo; Alexander Hull; Guillermo Martíne...; Nathan Woodling; Rosa Rademakers; Adrian M. Isaacs; Carlo Frigerio; Marka van Blitter...; Tammaryn Lashley; Teresa Niccoli
• Keywords: C9ORF72; XBP1; Vulnerability; Degradation

Neurodegenerative diseases are characterized by the localized loss of neurons. Why cell death is triggered only in specific neuronal populations and whether it response to toxic insults or initial cellular state that determines their vulnerability unknown. To understand individual responses disease, we profiled transcriptional signatures throughout disease development a Drosophila model C9orf72 (G4C2) repeat expansion (C9), most common genetic cause frontotemporal dementia amyotrophic lateral sclerosis. We identified specifically vulnerable resistant C9 expression found an upregulation protein homeostasis pathways neurons at baseline. Overexpression Xbp1s, key regulator unfolded central node resistance network, rescues toxicity. This study shows depends on intrinsic leveraging neurons' properties can boost