TY - JOUR
T1 - Hemizygous deletion of Tbk1 worsens neuromuscular junction pathology in TDP-43G298S transgenic mice
AU - Sieverding, Kirsten
AU - Ulmer, Johannes
AU - Bruno, Clara
AU - Satoh, Takashi
AU - Tsao, William
AU - Freischmidt, Axel
AU - Akira, Shizuo
AU - Wong, Philip C.
AU - Ludolph, Albert C.
AU - Danzer, Karin M.
AU - Lobsiger, Christian S.
AU - Brenner, David
AU - Weishaupt, Jochen H.
N1 - Funding Information:
This work was funded by the Baustein-Programm of the Medical Faculty of the University of Ulm ( LSBR.0030 to D. Brenner) and by The Bruno and Ilse Frick Foundation for ALS Research (to J.H. Weishaupt). The authors declare no competing financial interests.
Funding Information:
This work was funded by the Baustein-Programm of the Medical Faculty of the University of Ulm (LSBR.0030 to D. Brenner) and by The Bruno and Ilse Frick Foundation for ALS Research (to J.H. Weishaupt). The authors declare no competing financial interests.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2021/1
Y1 - 2021/1
N2 - 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.
AB - 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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U2 - 10.1016/j.expneurol.2020.113496
DO - 10.1016/j.expneurol.2020.113496
M3 - Article
C2 - 33038415
AN - SCOPUS:85093648473
SN - 0014-4886
VL - 335
JO - Experimental Neurology
JF - Experimental Neurology
M1 - 113496
ER -