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<p>Microglia and neuroinflammation are involved in amyotrophic lateral sclerosis (ALS), but the precise underlying molecular mechanisms remain elusive. We generated single-nuclei transcriptomes from the spinal cord and motor cortex of patients with sporadic ALS (sALS) and <i>C9orf72</i> ALS (C9-ALS). Here we confirmed that <i>C9orf72</i> is highly expressed in microglia and observed that the hexanucleotide repeat expansion (HRE) results in haploinsufficiency. Whereas sALS microglia transitioned toward disease-associated cell states, <i>C9orf72</i> HRE microglia exhibited a diminished response, with alterations in endolysosomal pathways. We confirmed these observations using a human microglia xenograft model, in which <i>C9orf72</i> mutations led to a reduced activation. We also confirmed the endolysosomal alterations in <i>C9orf72</i> HRE and <i>C9orf72</i>-deficient induced pluripotent stem cell (iPSC)-derived microglia. We also found a diminished response of <i>C9orf72</i> HRE astrocytes and provided a map of dysregulated ligand−receptor pairs in microglia and astrocytes. Our data highlight variations in the cellular substrate of sporadic and inherited forms of ALS, which have implications for patient stratification and selection of appropriate treatments.</p>

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C9orf72 hexanucleotide repeat expansions impair microglial response in ALS

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月14日

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  • Pegah Masrori,
  • Baukje Bijnens,
  • Laura Fumagalli,
  • Kristofer Davie,
  • Suresh Kumar Poovathingal,
  • Tim Meese,
  • Annet Storm,
  • Nicole Hersmus,
  • Raheem Fazal,
  • Diede van den Biggelaar,
  • Bob Asselbergh,
  • Roxane Gruel,
  • Johanna Van Den Daele,
  • Heidi Denton,
  • Paula Polanco Miquel,
  • Simona Manzella,
  • Winnok H. De Vos,
  • Siddhartan Chandran,
  • Ludo Van Den Bosch,
  • Dietmar Rudolf Thal,
  • Renzo Mancuso,
  • Philip Van Damme

摘要

Microglia and neuroinflammation are involved in amyotrophic lateral sclerosis (ALS), but the precise underlying molecular mechanisms remain elusive. We generated single-nuclei transcriptomes from the spinal cord and motor cortex of patients with sporadic ALS (sALS) and C9orf72 ALS (C9-ALS). Here we confirmed that C9orf72 is highly expressed in microglia and observed that the hexanucleotide repeat expansion (HRE) results in haploinsufficiency. Whereas sALS microglia transitioned toward disease-associated cell states, C9orf72 HRE microglia exhibited a diminished response, with alterations in endolysosomal pathways. We confirmed these observations using a human microglia xenograft model, in which C9orf72 mutations led to a reduced activation. We also confirmed the endolysosomal alterations in C9orf72 HRE and C9orf72-deficient induced pluripotent stem cell (iPSC)-derived microglia. We also found a diminished response of C9orf72 HRE astrocytes and provided a map of dysregulated ligand−receptor pairs in microglia and astrocytes. Our data highlight variations in the cellular substrate of sporadic and inherited forms of ALS, which have implications for patient stratification and selection of appropriate treatments.