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

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.

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Publication Details

Journal
Nature Communications
Published
2025-08-26
DOI
https://doi.org/10.1038/s41467-025-63211-w
Citations
3
Primary Topic
Neuroinflammation and Neurodegeneration Mechanisms
Type
article
Field-Weighted Citation Impact
2.53

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

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

Stéphanie Millecamps, Dávid Brenner, Nadège Sarrazin, Jacques Perronnet, Marie Coutelier, Raphaelle Cassel, Michel Mallat, Clementine Philibert, Hidemi Misawa, Julie Lameth, Delphine Bohl, M Ribon, Isadora Lenoël, Jochen Hans Weishaupt, Christian S. Lobsiger, Séverine Boillée, Coline Jost-Mousseau, Félicie Lorenc, Aurélien Diebold, David Robaldo, Manel Badsi
article en
3 citations

Abstract

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.

Nature CommunicationsVol. 16(1)
Boston University (US), Centre National de la Recherche Scientifique (FR), Inserm (FR), Délégation Paris 7 (FR), Universität Ulm (DE), Keio University (JP), German Center for Neurodegenerative Diseases (DE), Sorbonne Université (FR), Assistance Publique – Hôpitaux de Paris (FR), Pitié-Salpêtrière Hospital (FR), Institut du Cerveau (FR), UMS Phénotypage du petit animal (FR), Université de Strasbourg (FR)
Agence Nationale de la Recherche, Association pour la Recherche sur la Sclérose Latérale Amyotrophique et autres Maladies du Motoneurone, University of California, San Francisco
Reduced inequalities
Openalex Percentile: Top 10%
Neuroinflammation and Neurodegeneration Mechanisms
2.53
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