Journal Article

DZNE-2025-00990

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png ALS/FTD-linked TBK1 deficiency in microglia induces an aged-like microglial signature and drives social recognition deficits in mice.

Lenoel, I. ; Ribon, M. ; Lorenc, F. ; Diebold, A. ; Philibert, C. E. ; Robaldo, D. ; Badsi, M. ; Perronnet, J. ; Lameth, J. ; Berriat, F. ; Misawa, H. ; Coutelier, M. ; Cassel, R. ; Sarrazin, N. ; Jost-Mousseau, C. ; Bohl, D. ; Millecamps, S. ; Mallat, M. ; Brenner, D.DZNE* ; Weishaupt, J. H. ; Boillée, S. ; Lobsiger, C. S.

2025
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41467-025-63211-w

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.

Keyword(s): Animals (MeSH) ; Protein Serine-Threonine Kinases: genetics (MeSH) ; Protein Serine-Threonine Kinases: deficiency (MeSH) ; Protein Serine-Threonine Kinases: metabolism (MeSH) ; Microglia: metabolism (MeSH) ; Microglia: pathology (MeSH) ; Amyotrophic Lateral Sclerosis: genetics (MeSH) ; Amyotrophic Lateral Sclerosis: pathology (MeSH) ; Amyotrophic Lateral Sclerosis: metabolism (MeSH) ; Mice (MeSH) ; Frontotemporal Dementia: genetics (MeSH) ; Frontotemporal Dementia: metabolism (MeSH) ; Frontotemporal Dementia: pathology (MeSH) ; Motor Neurons: metabolism (MeSH) ; Motor Neurons: pathology (MeSH) ; Mice, Knockout (MeSH) ; Spinal Cord: pathology (MeSH) ; Spinal Cord: metabolism (MeSH) ; Male (MeSH) ; Autophagy (MeSH) ; Disease Models, Animal (MeSH) ; Female (MeSH) ; Mice, Inbred C57BL (MeSH) ; Aging (MeSH) ; Brain: pathology (MeSH) ; Brain: metabolism (MeSH) ; Humans (MeSH) ; Protein Serine-Threonine Kinases ; Tbk1 protein, mouse

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Contributing Institute(s):

1. Clinical Study Center (Ulm) (Clinical Study Center (Ulm))

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2025

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