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

Abstract

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.

• Authors: 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
• Journal: Experimental neurology (Exp Neurol) Vol. 335 Pg. 113496 (01 2021) ISSN: 1090-2430 [Electronic] United States
• PMID: 33038415 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• DNA-Binding Proteins
• TARDBP protein, human
• Tbk1 protein, mouse
• Protein Serine-Threonine Kinases

Topics

• Amyotrophic Lateral Sclerosis (genetics, pathology)
• Animals
• DNA-Binding Proteins (genetics)
• Gene Deletion
• Gliosis (genetics)
• Humans
• Immunohistochemistry
• Mice
• Mice, Knockout
• Mice, Transgenic
• Motor Neurons (pathology)
• Movement Disorders (genetics, pathology)
• Muscle Denervation
• Mutation
• Neuromuscular Junction (pathology)
• Protein Serine-Threonine Kinases (genetics)
• Spinal Cord (pathology)