Hemizygous deletion of Tbk1 worsens neuromuscular junction pathology in TDP-43 G298S 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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Bibliographic Details
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
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Summary: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.
ISSN:1090-2430