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<p>TANK-Binding Kinase 1 (<i>TBK1</i>) is involved in autophagy and immune signaling. Dominant loss-of-function mutations in <i>TBK1</i> have been linked to Amyotrophic Lateral Sclerosis (ALS), Fronto-temporal dementia (FTD), and ALS/FTD. However, pathogenic mechanisms remain unclear, particularly the cell-type specific disease contributions of <i>TBK1</i> mutations. Here, we show that deleting <i>Tbk1</i> from mouse motor neurons does not induce transcriptional stress, despite lifelong signs of autophagy deregulations. Conversely, <i>Tbk1</i> deletion in microglia alters their homeostasis and reactive responses. In both spinal cord and brain, <i>Tbk1</i> deletion leads to a pro-inflammatory, primed microglial signature with features of ageing and neurodegeneration. While it does not induce or modify ALS-like motor neuron damage, microglial <i>Tbk1</i> deletion is sufficient to cause early FTD-like social recognition deficits. This phenotype is linked to focal microglial activation and T cell infiltration in the substantia nigra <i>pars reticulata</i> and pallidum. Our results reveal that part of <i>TBK1</i>-linked FTD disease originates from microglial dysfunction.</p>

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ALS/FTD-linked TBK1 deficiency in microglia induces an aged-like microglial signature and drives social recognition deficits in mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月26日

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  • Isadora Lenoel,
  • Matthieu Ribon,
  • Félicie Lorenc,
  • Aurélien Diebold,
  • Clementine E. Philibert,
  • David Robaldo,
  • Manel Badsi,
  • Julianne Perronnet,
  • Julie Lameth,
  • Felix Berriat,
  • Hidemi Misawa,
  • Marie Coutelier,
  • Raphaelle Cassel,
  • Nadège Sarrazin,
  • Coline Jost-Mousseau,
  • Delphine Bohl,
  • Stéphanie Millecamps,
  • Michel Mallat,
  • David Brenner,
  • Jochen H. Weishaupt,
  • Séverine Boillée,
  • Christian S. Lobsiger

摘要

TANK-Binding Kinase 1 (TBK1) is involved in autophagy and immune signaling. Dominant loss-of-function mutations in TBK1 have been linked to Amyotrophic Lateral Sclerosis (ALS), Fronto-temporal dementia (FTD), and ALS/FTD. However, pathogenic mechanisms remain unclear, particularly the cell-type specific disease contributions of TBK1 mutations. Here, we show that deleting Tbk1 from mouse motor neurons does not induce transcriptional stress, despite lifelong signs of autophagy deregulations. Conversely, Tbk1 deletion in microglia alters their homeostasis and reactive responses. In both spinal cord and brain, Tbk1 deletion leads to a pro-inflammatory, primed microglial signature with features of ageing and neurodegeneration. While it does not induce or modify ALS-like motor neuron damage, microglial Tbk1 deletion is sufficient to cause early FTD-like social recognition deficits. This phenotype is linked to focal microglial activation and T cell infiltration in the substantia nigra pars reticulata and pallidum. Our results reveal that part of TBK1-linked FTD disease originates from microglial dysfunction.