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<p>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&#xa0;male <i>Sod1</i><sup>G86R</sup> 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<sup>R119G</sup> (rs11538707) as a positive disease modifier in ALS. Through gain of function, CREB3<sup>R119G</sup> decreases the risk of developing ALS and the motor progression rate of ALS patients.</p>

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CREB3 gain of function variants protect against ALS

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月26日

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  • 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

摘要

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.