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 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.
Authors
- Alexander Hull (ORCID: https://orcid.org/0000-0002-9700-4926)
- Carlo Sala Frigerio (ORCID: https://orcid.org/0000-0003-4038-6449)
- Guillermo Martínez-Corrales (ORCID: https://orcid.org/0000-0002-3923-5902)
- Sharifah Anoar (ORCID: https://orcid.org/0000-0003-4925-6798)
- Nathaniel S. Woodling (ORCID: https://orcid.org/0000-0002-0298-3800)
- Dunxin Shen (ORCID: https://orcid.org/0000-0001-6771-9114)
- Rosa Rademakers (ORCID: https://orcid.org/0000-0002-4049-0863)
- Tammaryn Lashley (ORCID: https://orcid.org/0000-0001-7389-0348)
- David Osumi-Sutherland (ORCID: https://orcid.org/0000-0002-7073-9172)
- Yazead Buhidma (ORCID: https://orcid.org/0000-0002-6689-4508)
- Benjamin Aleyakpo
- Adrian M. Isaacs (ORCID: https://orcid.org/0000-0002-6820-5534)
- Alec Vincent (ORCID: https://orcid.org/0000-0002-9201-2900)
- Marka van Blitterswijk (ORCID: https://orcid.org/0000-0002-3054-7053)
- Dongwei Xu (ORCID: https://orcid.org/0000-0001-9802-0664)
- Mireia Carcolé (ORCID: https://orcid.org/0000-0001-5054-9016)
- Elli Tsintzas
- Marie Maeland (ORCID: https://orcid.org/0009-0009-9073-1088)
- Teresa Niccoli (ORCID: https://orcid.org/0000-0001-9337-0411)
- Evan Udine
Institutions
- Wellcome Sanger Institute (GB)
- UK Dementia Research Institute (GB)
- VIB-UAntwerp Center for Molecular Neurology (BE)
- Mayo Clinic in Florida (US)
- National Hospital for Neurology and Neurosurgery (GB)
- University College London (GB)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-04-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.115459
- Citations
- 3
- Primary Topic
- Genetics and Neurodevelopmental Disorders
- Type
- article
- Field-Weighted Citation Impact
- 5.45