LAUSR

Background TANK-binding kinase1 (TBK1) haploinsufficiency has been shown to cause both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD); however, the mechanism is unclear. Methods Myeloid Tbk1 knockout mice (Tbk1-LKO mice) were established and motor function and pathological analyses were also performed. The level of p-TBK1 was analyzed in the ALS animal model and in patient samples using flow cytometry. The expression of inflammatory proteins and mRNAs was analyzed via western blotting and RT-PCR, respectively. Results The latency to fall in seven-month-old Tbk1-LKO mice was significantly reduced in evaluations conducted on two consecutive days. Overall, 25.6% of Tbk1-LKO mice presented paralysis symptoms and signs, along with a loosened myelin sheath and axon degeneration at 14–16 months of age. Furthermore, the Tbk1 deficiency in myeloid cells induced inflammatory cell infiltration and dysbacteriosis in the digestive tract. Additionally, p-TBK1 levels were reduced by 29.5% and 14.8% in monocytes of patients with definite ALS and probable ALS and decreased by 27.6% and 45.5% in monocytes and microglia of ALS animals, respectively. The use of PEI-mannose-TBK1 or PEI-mannose-SaCas9-sgRNA to delete mutant SOD1 in macrophages significantly delayed disease onset and prolonged survival in the mouse model of ALS. Conclusions Based on these data, inflammatory monocyte and macrophage infiltration and impaired innate immune defenses contribute to ALS and FTD.