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

• Published in: Experimental neurology Vol. 335
• Main Authors: Sieverding, Kirsten, Ulmer, Johannes, Bruno, Clara, Satoh, Takashi, Tsao, William, Freischmidt, Axel, Akira, Shizuo, Wong, Philip C., Ludolph, Albert C., Danzer, Karin M., Lobsiger, Christian S., Brenner, David, Weishaupt, Jochen H.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.01.2021
• Subjects: sALS; MN; LoF; ALS; CNS; NMJ; fALS; SOD1; MFI; TBK1; FTD; TDP-43 / TARDBP; LSC; wt
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2020.113496

Mutations in the genes TARDBP (encoding the TDP-43 protein) and TBK1 can cause familial ALS. Neuronal cytoplasmatic accumulations of the misfolded, hyperphosphorylated 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-43G298S 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-43G298S transgenic mice, as similarly observed in the SOD1G93A transgenic mouse model for ALS before. Conclusively, our findings suggest that TBK1 mutations can affect the neuromuscular synapse. [Display omitted] •Tbk1 deletion affects NMJ integrity but not neuron loss in TDP-43G298S mutant mice.•Heterozygous loss of Tbk1 tends to slightly worsen motor dysfunction of TDP-43G298S transgenic mice.•Hemizygosity of Tbk1 does not alter TDP-43 pathology in TDP-43G298S transgenic mice.•Tbk1 haploinsufficiency does not modify glial activation in TDP-43G298S mutant mice.