TY  - JOUR
AU  - Lenoel, Isadora
AU  - Ribon, Matthieu
AU  - Lorenc, Félicie
AU  - Diebold, Aurélien
AU  - Philibert, Clementine E
AU  - Robaldo, David
AU  - Badsi, Manel
AU  - Perronnet, Julianne
AU  - Lameth, Julie
AU  - Berriat, Felix
AU  - Misawa, Hidemi
AU  - Coutelier, Marie
AU  - Cassel, Raphaelle
AU  - Sarrazin, Nadège
AU  - Jost-Mousseau, Coline
AU  - Bohl, Delphine
AU  - Millecamps, Stéphanie
AU  - Mallat, Michel
AU  - Brenner, David
AU  - Weishaupt, Jochen H
AU  - Boillée, Séverine
AU  - Lobsiger, Christian S
TI  - ALS/FTD-linked TBK1 deficiency in microglia induces an aged-like microglial signature and drives social recognition deficits in mice.
JO  - Nature Communications
VL  - 16
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Springer Nature
M1  - DZNE-2025-00990
SP  - 7951
PY  - 2025
AB  - 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.
KW  - Animals
KW  - Protein Serine-Threonine Kinases: genetics
KW  - Protein Serine-Threonine Kinases: deficiency
KW  - Protein Serine-Threonine Kinases: metabolism
KW  - Microglia: metabolism
KW  - Microglia: pathology
KW  - Amyotrophic Lateral Sclerosis: genetics
KW  - Amyotrophic Lateral Sclerosis: pathology
KW  - Amyotrophic Lateral Sclerosis: metabolism
KW  - Mice
KW  - Frontotemporal Dementia: genetics
KW  - Frontotemporal Dementia: metabolism
KW  - Frontotemporal Dementia: pathology
KW  - Motor Neurons: metabolism
KW  - Motor Neurons: pathology
KW  - Mice, Knockout
KW  - Spinal Cord: pathology
KW  - Spinal Cord: metabolism
KW  - Male
KW  - Autophagy
KW  - Disease Models, Animal
KW  - Female
KW  - Mice, Inbred C57BL
KW  - Aging
KW  - Brain: pathology
KW  - Brain: metabolism
KW  - Humans
KW  - Protein Serine-Threonine Kinases (NLM Chemicals)
KW  - Tbk1 protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40858618
C2  - pmc:PMC12381211
DO  - DOI:10.1038/s41467-025-63211-w
UR  - https://pub.dzne.de/record/280906
ER  -