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; Caroline Rouaux

doi:10.1038/s41467-025-58098-6

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 DupuisCaroline Rouaux^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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 Sod1^G86R 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 CREB3^R119G (rs11538707) as a positive disease modifier in ALS. Through gain of function, CREB3^R119G decreases the risk of developing ALS and the motor progression rate of ALS patients.

Original language	English
Article number	2942
Journal	Nature Communications
Volume	16
Issue number	1
DOIs	https://doi.org/10.1038/s41467-025-58098-6
Publication status	Published - 26 Mar 2025

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Megat, S., Marques, C., Hernán-Godoy, M., Sellier, C., Stuart-Lopez, G., Dirrig-Grosch, S., Gorin, C., Brunet, A., Fischer, M., Keime, C., Kessler, P., Mendoza-Parra, M. A., Zwamborn, R. A. J., Veldink, J. H., Scholz, S. W., Ferrucci, L., Ludolph, A., Traynor, B., Chio, A., ... Rouaux, C. (2025). CREB3 gain of function variants protect against ALS. Nature Communications, 16(1), Article 2942. https://doi.org/10.1038/s41467-025-58098-6

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title = "CREB3 gain of function variants protect against ALS",

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.",

author = "Salim Megat and Christine Marques and Marina Hern{\'a}n-Godoy and Chantal Sellier and Geoffrey Stuart-Lopez and Sylvie Dirrig-Grosch and Charlotte Gorin and Aurore Brunet and Mathieu Fischer and C{\'e}line Keime and Pascal Kessler and Mendoza-Parra, {Marco Antonio} and Zwamborn, {Ramona A.J.} and Veldink, {Jan H.} and Scholz, {Sonja W.} and Luigi Ferrucci and Albert Ludolph and Bryan Traynor and Adriano Chio and Luc Dupuis and Caroline Rouaux",

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Megat, S, Marques, C, Hernán-Godoy, M, Sellier, C, Stuart-Lopez, G, Dirrig-Grosch, S, Gorin, C, Brunet, A, Fischer, M, Keime, C, Kessler, P, Mendoza-Parra, MA, Zwamborn, RAJ, Veldink, JH, Scholz, SW, Ferrucci, L, Ludolph, A, Traynor, B, Chio, A, Dupuis, L & Rouaux, C 2025, 'CREB3 gain of function variants protect against ALS', Nature Communications, vol. 16, no. 1, 2942. https://doi.org/10.1038/s41467-025-58098-6

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AU - Megat, Salim

AU - Marques, Christine

AU - Hernán-Godoy, Marina

AU - Sellier, Chantal

AU - Stuart-Lopez, Geoffrey

AU - Dirrig-Grosch, Sylvie

AU - Gorin, Charlotte

AU - Brunet, Aurore

AU - Fischer, Mathieu

AU - Keime, Céline

AU - Kessler, Pascal

AU - Mendoza-Parra, Marco Antonio

AU - Zwamborn, Ramona A.J.

AU - Veldink, Jan H.

AU - Scholz, Sonja W.

AU - Ferrucci, Luigi

AU - Ludolph, Albert

AU - Traynor, Bryan

AU - Chio, Adriano

AU - Dupuis, Luc

AU - Rouaux, Caroline

PY - 2025/3/26

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N2 - 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.

AB - 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.

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JO - Nature Communications

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CREB3 gain of function variants protect against ALS

Abstract

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