| First Author | Sieverding K | Year | 2021 |
| Journal | Exp Neurol | Volume | 335 |
| Pages | 113496 | PubMed ID | 33038415 |
| Mgi Jnum | J:301266 | Mgi Id | MGI:6503409 |
| Doi | 10.1016/j.expneurol.2020.113496 | Citation | Sieverding K, et al. (2021) Hemizygous deletion of Tbk1 worsens neuromuscular junction pathology in TDP-43(G298S) transgenic mice. Exp Neurol 335:113496 |
| abstractText | 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(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. |
