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

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 and Christian S. Lobsiger ()
Additional contact information
Isadora Lenoel: Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, APHP, Hôpital de la Pitié-Salpêtrière
Matthieu Ribon: Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, APHP, Hôpital de la Pitié-Salpêtrière
Félicie Lorenc: Université de Strasbourg, Inserm, UMR-S 1329, Strasbourg Translational Neuroscience and Psychiatry, CRBS
Aurélien Diebold: Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, APHP, Hôpital de la Pitié-Salpêtrière
Clementine E. Philibert: Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, APHP, Hôpital de la Pitié-Salpêtrière
David Robaldo: Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, APHP, Hôpital de la Pitié-Salpêtrière
Manel Badsi: Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, APHP, Hôpital de la Pitié-Salpêtrière
Julianne Perronnet: Sorbonne Université, UMS 28, Phénotypage du petit animal
Julie Lameth: Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, APHP, Hôpital de la Pitié-Salpêtrière
Felix Berriat: Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, APHP, Hôpital de la Pitié-Salpêtrière
Hidemi Misawa: Keio University
Marie Coutelier: Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, APHP, Hôpital de la Pitié-Salpêtrière
Raphaelle Cassel: Université de Strasbourg, Inserm, UMR-S 1329, Strasbourg Translational Neuroscience and Psychiatry, CRBS
Nadège Sarrazin: Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, APHP, Hôpital de la Pitié-Salpêtrière
Coline Jost-Mousseau: Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, APHP, Hôpital de la Pitié-Salpêtrière
Delphine Bohl: Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, APHP, Hôpital de la Pitié-Salpêtrière
Stéphanie Millecamps: Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, APHP, Hôpital de la Pitié-Salpêtrière
Michel Mallat: Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, APHP, Hôpital de la Pitié-Salpêtrière
David Brenner: University of Ulm
Jochen H. Weishaupt: University of Ulm
Séverine Boillée: Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, APHP, Hôpital de la Pitié-Salpêtrière
Christian S. Lobsiger: Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, APHP, Hôpital de la Pitié-Salpêtrière

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-63211-w

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