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, 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 pathoge...
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| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
2021
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| In: |
Experimental neurology
Year: 2020, Volume: 335, Pages: 1-14 |
| ISSN: | 1090-2430 |
| DOI: | 10.1016/j.expneurol.2020.113496 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.expneurol.2020.113496 Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S0014488620303277 
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| Author Notes: | Kirsten Sieverding, Johannes Ulmer, Clara Bruno, Takashi Satoh, William Tsao, Axel Freischmidt, Shizuo Akira, Philip C. Wong, Albert C. Ludolph, Karin M. Danzer, Christian S. Lobsiger, David Brenner, Jochen H. Weishaupt |
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| 245 | 1 | 0 | |a Hemizygous deletion of Tbk1 worsens neuromuscular junction pathology in TDP-43G298S transgenic mice |c Kirsten Sieverding, Johannes Ulmer, Clara Bruno, Takashi Satoh, William Tsao, Axel Freischmidt, Shizuo Akira, Philip C. Wong, Albert C. Ludolph, Karin M. Danzer, Christian S. Lobsiger, David Brenner, Jochen H. Weishaupt |
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| 520 | |a 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. | ||
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