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J Exp Med. 2019 Feb 4;216(2):267-278. doi: 10.1084/jem.20180729. Epub 2019 Jan 11.

Heterozygous Tbk1 loss has opposing effects in early and late stages of ALS in mice.

Author information

1
Department of Neurology, University of Ulm, Ulm, Germany.
2
Institute of Clinical Neurobiology, University Hospital of Wuerzburg, Wuerzburg, Germany.
3
Institut du Cerveau et de la Moelle Épinière, Institut National de la Santé et de la Recherche Médicale Unité 1127, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7225, Sorbonne Université, Paris, France.
4
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
5
Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany.
6
Department of Neurology, University of Ulm, Ulm, Germany jochen.weishaupt@uni-ulm.de.

Abstract

Heterozygous loss-of-function mutations of TANK-binding kinase 1 (TBK1 ) cause familial ALS, yet downstream mechanisms of TBK1 mutations remained elusive. TBK1 is a pleiotropic kinase involved in the regulation of selective autophagy and inflammation. We show that heterozygous Tbk1 deletion alone does not lead to signs of motoneuron degeneration or disturbed autophagy in mice during a 200-d observation period. Surprisingly, however, hemizygous deletion of Tbk1 inversely modulates early and late disease phases in mice additionally overexpressing ALS-linked SOD1G93A , which represents a "second hit" that induces both neuroinflammation and proteostatic dysregulation. At the early stage, heterozygous Tbk1 deletion impairs autophagy in motoneurons and prepones both the clinical onset and muscular denervation in SOD1G93A/Tbk1+/- mice. At the late disease stage, however, it significantly alleviates microglial neuroinflammation, decelerates disease progression, and extends survival. Our results indicate a profound effect of TBK1 on brain inflammatory cells under pro-inflammatory conditions and point to a complex, two-edged role of TBK1 in SOD1-linked ALS.

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