CREB3 gain of function variants protect against ALS

Salim Megat (), Christine Marques, Marina Hernán-Godoy, Chantal Sellier, Geoffrey Stuart-Lopez, Sylvie Dirrig-Grosch, Charlotte Gorin, Aurore Brunet, Mathieu Fischer, Céline Keime, Pascal Kessler, Marco Antonio Mendoza-Parra, Ramona A. J. Zwamborn, Jan H. Veldink, Sonja W. Scholz, Luigi Ferrucci, Albert Ludolph, Bryan Traynor, Adriano Chio, Luc Dupuis and Caroline Rouaux ()
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Salim Megat: Centre de Recherche en Biomédecine de Strasbourg
Christine Marques: Centre de Recherche en Biomédecine de Strasbourg
Marina Hernán-Godoy: Centre de Recherche en Biomédecine de Strasbourg
Chantal Sellier: Centre de Recherche en Biomédecine de Strasbourg
Geoffrey Stuart-Lopez: Centre de Recherche en Biomédecine de Strasbourg
Sylvie Dirrig-Grosch: Centre de Recherche en Biomédecine de Strasbourg
Charlotte Gorin: Centre de Recherche en Biomédecine de Strasbourg
Aurore Brunet: Centre de Recherche en Biomédecine de Strasbourg
Mathieu Fischer: Centre de Recherche en Biomédecine de Strasbourg
Céline Keime: Biologie Moléculaire et Cellulaire
Pascal Kessler: Centre de Recherche en Biomédecine de Strasbourg
Marco Antonio Mendoza-Parra: University Paris-Saclay
Ramona A. J. Zwamborn: University Medical Centre Utrecht
Jan H. Veldink: University Medical Centre Utrecht
Sonja W. Scholz: National Institute of Neurological Disorders and Stroke
Luigi Ferrucci: NIH
Albert Ludolph: Ulm University
Bryan Traynor: Johns Hopkins University Medical Center
Adriano Chio: University of Turin
Luc Dupuis: Centre de Recherche en Biomédecine de Strasbourg
Caroline Rouaux: Centre de Recherche en Biomédecine de Strasbourg

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly evolving neurodegenerative disease arising from the loss of glutamatergic corticospinal neurons (CSN) and cholinergic motoneurons (MN). Here, we performed comparative cross-species transcriptomics of CSN using published snRNA-seq data from the motor cortex of ALS and control postmortem tissues, and performed longitudinal RNA-seq on CSN purified from male Sod1G86R mice. We report that CSN undergo ER stress and altered mRNA translation, and identify the transcription factor CREB3 and its regulatory network as a resilience marker of ALS, not only amongst vulnerable neuronal populations, but across all neuronal populations as well as other cell types. Using genetic and epidemiologic analyses we further identify the rare variant CREB3R119G (rs11538707) as a positive disease modifier in ALS. Through gain of function, CREB3R119G decreases the risk of developing ALS and the motor progression rate of ALS patients.

Date: 2025
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DOI: 10.1038/s41467-025-58098-6

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