The Loss of TBK1 Kinase Activity in Motor Neurons or in All Cell Types Differentially Impacts ALS Disease Progression in SOD1 Mice

DNA sequence variants in the TBK1 gene associate with or cause sporadic or familial amyotrophic lateral sclerosis (ALS). Here we show that mice bearing human ALS-associated TBK1 missense loss-of-function mutations, or mice in which the Tbk1 gene is selectively deleted in motor neurons, do not display a neurodegenerative disease phenotype. However, loss of TBK1 function in motor neurons of the SOD1G93A mouse model of ALS impairs autophagy, increases SOD1 aggregation, and accelerates early disease onset without affecting lifespan. By contrast, point mutations that decrease TBK1 kinase activity in all cells also accelerate disease onset but extend the lifespan of SOD1 mice. This difference correlates with the failure to activate high levels of expression of interferon-inducible genes in glia. We conclude that loss of TBK1 kinase activity impacts ALS disease progression through distinct pathways in different spinal cord cell types and further implicate the importance of glia in neurodegeneration. Dissection of pathways affected by TBK1 loss of function mutations in the ALS spinal cord

TBK1基因的DNA序列变异与散发性或家族性肌萎缩侧索硬化（amyotrophic lateral sclerosis, ALS）相关，或直接致病。本研究发现，携带人类ALS相关TBK1错义型功能丧失突变的小鼠，或是运动神经元（motor neurons）中Tbk1基因特异性敲除的小鼠，均未表现出神经退行性疾病表型。然而，在ALS的SOD1G93A小鼠模型的运动神经元中敲除TBK1功能，会损伤自噬（autophagy）功能、加剧SOD1聚集，并加速疾病早期发作，但不影响小鼠寿命。与之相反，在所有细胞中引入降低TBK1激酶活性（kinase activity）的点突变，虽同样可加速疾病发作，却能延长SOD1小鼠的生存期。该差异与胶质细胞（glia）无法高效激活干扰素诱导基因（interferon-inducible genes）的表达密切相关。综上，TBK1激酶活性缺失通过不同脊髓细胞类型中的特异性信号通路影响ALS疾病进程，并进一步凸显了胶质细胞在神经退行性变中的重要作用。本研究对ALS脊髓中TBK1功能丧失突变所调控的信号通路进行了解析。