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

• Published in: Experimental neurology 2021-01, Vol.335, p.113496
• 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: Article
• Language: English
• Subjects: Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - pathology; Animals; DNA-Binding Proteins - genetics; Gene Deletion; Gliosis - genetics; Humans; Immunohistochemistry; Mice; Mice, Knockout; Mice, Transgenic; Motor Neurons - pathology; Movement Disorders - genetics; Movement Disorders - pathology; Muscle Denervation; Mutation; Neuromuscular Junction - pathology; Protein-Serine-Threonine Kinases - genetics; Spinal Cord - pathology
• ISSN: 1090-2430

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-43 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 transgenic mice, as similarly observed in the SOD1 transgenic mouse model for ALS before. Conclusively, our findings suggest that TBK1 mutations can affect the neuromuscular synapse.