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

The Journal of experimental medicine, 2019-02, Vol.216 (2), p.267-278 [Peer Reviewed Journal]

2019 Brenner et al. ;Distributed under a Creative Commons Attribution 4.0 International License ;2019 Brenner et al. 2019 ;ISSN: 0022-1007 ;EISSN: 1540-9538 ;DOI: 10.1084/jem.20180729 ;PMID: 30635357

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Title:
Heterozygous Tbk1 loss has opposing effects in early and late stages of ALS in mice
Author: Brenner, David ; Sieverding, Kirsten ; Bruno, Clara ; Lüningschrör, Patrick ; Buck, Eva ; Mungwa, Simon ; Fischer, Lena ; Brockmann, Sarah J ; Ulmer, Johannes ; Bliederhäuser, Corinna ; Philibert, Clémentine E ; Satoh, Takashi ; Akira, Shizuo ; Boillée, Séverine ; Mayer, Benjamin ; Sendtner, Michael ; Ludolph, Albert C ; Danzer, Karin M ; Lobsiger, Christian S ; Freischmidt, Axel ; Weishaupt, Jochen H
Subjects: Amyotrophic Lateral Sclerosis ; Amyotrophic Lateral Sclerosis - genetics ; Amyotrophic Lateral Sclerosis - metabolism ; Amyotrophic Lateral Sclerosis - pathology ; Animals ; Autophagic Cell Death ; Autophagic Cell Death - genetics ; Brain ; Brain - metabolism ; Brain - pathology ; Disease Models, Animal ; Gene Deletion ; Life Sciences ; Loss of Function Mutation ; Mice ; Mice, Knockout ; Microglia ; Microglia - metabolism ; Microglia - pathology ; Motor Neurons ; Motor Neurons - metabolism ; Motor Neurons - pathology ; Protein Serine-Threonine Kinases ; Protein Serine-Threonine Kinases - genetics ; Protein Serine-Threonine Kinases - metabolism ; Superoxide Dismutase ; Superoxide Dismutase - genetics ; Superoxide Dismutase - metabolism ; Superoxide Dismutase-1 ; Superoxide Dismutase-1 - genetics ; Superoxide Dismutase-1 - metabolism
Is Part Of: The Journal of experimental medicine, 2019-02, Vol.216 (2), p.267-278
Description: Heterozygous loss-of-function mutations of ( cause familial ALS, yet downstream mechanisms of mutations remained elusive. TBK1 is a pleiotropic kinase involved in the regulation of selective autophagy and inflammation. We show that heterozygous 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 inversely modulates early and late disease phases in mice additionally overexpressing ALS-linked , which represents a "second hit" that induces both neuroinflammation and proteostatic dysregulation. At the early stage, heterozygous deletion impairs autophagy in motoneurons and prepones both the clinical onset and muscular denervation in 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 -linked ALS.
Publisher: United States: Rockefeller University Press
Language: English
Identifier: ISSN: 0022-1007
EISSN: 1540-9538
DOI: 10.1084/jem.20180729
PMID: 30635357
Source: Hyper Article en Ligne (HAL) (Open Access)
GFMER Free Medical Journals
MEDLINE
PubMed Central

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

2019 Brenner et al. ;Distributed under a Creative Commons Attribution 4.0 International License ;2019 Brenner et al. 2019 ;ISSN: 0022-1007 ;EISSN: 1540-9538 ;DOI: 10.1084/jem.20180729 ;PMID: 30635357

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