Hemizygous deletion of Tbk1 worsens neuromuscular junction pathology in TDP-43G298S transgenic mice

Mutations in the genes TARDBP (encoding the TDP-43 protein) and TBK1 can cause familial ALS. Neuronal cytoplasmatic accumulations of the misfolded, hyper-phosphorylated RNA-binding protein TDP-43 are the pathological hallmark of most ALS cases and have been suggested to be a key aspect of ALS pathogenesis. Pharmacological induction of autophagy has been shown to reduce mutant TDP-43 aggregates and alleviate motor deficits in mice. TBK1 is exemplary for several other ALS genes that regulate autophagy. Consequently, we employed double mutant mice with both a heterozygous Tbk1 deletion and transgenic expression of human TDP-43(G298S) to test the hypothesis that impaired autophagy reduces intracellular clearance of an aggregation-prone protein and enhances toxicity of mutant TDP-43. The heterozygous deletion of Tbk1 did not change expression or cellular distribution of TDP-43 protein, motor neuron loss or reactive gliosis in the spinal cord of double-mutant mice at the age of 19 months. However, it aggravated muscle denervation and, albeit to a small and variable degree, motor dysfunction in TDP-43(G298S) transgenic mice, as similarly observed in the SOD1(G93A) transgenic mouse model for ALS before. Conclusively, our findings suggest that TBK1 mutations can affect the neuromuscular synapse.

Automated summary

Mutations in TARDBP and TBK1 genes can cause familial ALS, with accumulation of TDP-43 protein being a key pathological hallmark. Pharmacological induction of autophagy reduces mutant TDP-43 aggregates and may alleviate motor deficits. Several ALS genes, including TBK1, regulate autophagy, suggesting a potential therapeutic target for ALS.