Motor injury is caused by TBK1 deficiency in the myeloid cell and rescued by PEI-manose-TBK1

Background: TBK1 haploinsufficiency has been shown to cause both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD); however, the mechanism is unclear. Methods: A myeloid Tbk1 knockout mice (Tbk1-LKO mice) was established. Motor functional and pathological analyses were also performed. The p-TBK1 was tested by flow cytometry in the ALS animal model and patients. The inflammatory proteins and mRNA was analyzed by Western blot and RT-PCR. Results: We found that the latency to fall in seven-month-old Tbk1-LKO mice was significantly reduced on evaluation 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, Tbk1 deficiency in myeloid cells induced inflammatory cell infiltration and dysbacteriosis in the digestive tract. Additionally, p-Tbk1 content was reduced by 29.5% and 14.8% in monocytes of definite ALS and probable ALS patients and decreased by 27.6% and 45.5% in the monocytes and microglia of ALS animals, respectively. PEI-mannose-TBK1 or PEI-mannose-SaCas9-sgRNA for deleting mutant SOD1 in macrophages significantly delayed disease onset and prolonged survival in the ALS mouse model. Conclusions: These data suggest that inflammatory monocyte and macrophage infiltration and impaired innate immune defense are contributing factors to ALS and FTD.