ALS/FTD-linked TBK1 deficiency in microglia induces an aged-like microglial signature and drives social recognition deficits [Microdissected_Motor Neurons]

TANK-Binding Kinase 1 (TBK1) is involved in autophagy and immune signaling. Dominant loss-of-function mutations in TBK1 are 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 focus on cell-specific Tbk1 deletion in motor neurons or microglia. We find 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 causes 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. Laser-microdissected motor neurons from the spinal cord of aged mice (20 months) from different genotypes : deletion of Tbk1 specifically in motor neurons of respectively 0 Tbk1 allele (WT), or 2 Tbk1 alleles (KO). Tbk1fl/fl, Cx3CR1-Cre- mice = WT; Tbk1fl/fl, Cx3CR1-Cre+ = KO. Biological replicates (mice) are 6 per genotype

TANK结合激酶1（TANK-Binding Kinase 1, TBK1）参与自噬与免疫信号传导过程。TBK1的显性功能丧失突变与肌萎缩侧索硬化症（Amyotrophic Lateral Sclerosis, ALS）、额颞叶痴呆（Fronto-temporal dementia, FTD）及ALS/FTD重叠综合征密切相关。然而其致病机制仍有待阐明，尤其是TBK1突变的细胞类型特异性疾病贡献。本研究聚焦于运动神经元（motor neurons）或小胶质细胞（microglia）中Tbk1的细胞特异性敲除模型。实验结果显示，尽管小鼠运动神经元中存在终身性的自噬失调征象，但敲除运动神经元内的Tbk1并不会诱导转录应激反应。与之相反，小胶质细胞中Tbk1缺失会破坏其稳态平衡并改变其活化应答模式。在脊髓与大脑组织中，Tbk1缺失均可诱导产生促炎致敏型小胶质细胞特征谱，兼具衰老与神经退行性病变的相关表型。尽管该操作不会诱导或改变类ALS运动神经元损伤，但小胶质细胞Tbk1缺失会引发早期类FTD的社交识别障碍。该表型与黑质网状部与苍白球内的局灶性小胶质细胞活化及T细胞浸润密切相关。本研究结果揭示，部分与TBK1相关的FTD疾病起源于小胶质细胞功能异常。本数据集包含来自不同基因型20月龄老年小鼠脊髓的激光捕获显微切割（Laser-microdissected）运动神经元：分别为在运动神经元中特异性敲除0个Tbk1等位基因的野生型，以及敲除2个Tbk1等位基因的敲除型。具体分组如下：Tbk1fl/fl、Cx3CR1-Cre- 小鼠为野生型；Tbk1fl/fl、Cx3CR1-Cre+ 小鼠为敲除型。每组基因型的生物学重复（小鼠）数量为6只。