Haploinsufficiency of TANK-binding kinase 1 prepones age-associated neuroinflammatory changes without causing motor neuron degeneration in aged mice.

Autor:	Bruno C; Department of Neurology, University of Ulm, 89081 Ulm, Germany., Sieverding K; Department of Neurology, University of Ulm, 89081 Ulm, Germany., Freischmidt A; Department of Neurology, University of Ulm, 89081 Ulm, Germany., Satoh T; Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan., Walther P; Central Facility for Electron Microscopy, University of Ulm, 89081 Ulm, Germany., Mayer B; Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany., Ludolph AC; Department of Neurology, University of Ulm, 89081 Ulm, Germany., Akira S; Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan., Yilmazer-Hanke D; Department of Neurology, Clinical Neuroanatomy, Neurology, University of Ulm, 89081 Ulm, Germany., Danzer KM; Department of Neurology, University of Ulm, 89081 Ulm, Germany., Lobsiger CS; Institut du Cerveau et de la Moelle Épinière, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Sorbonne Université, 75013 Paris, France., Brenner D; Department of Neurology, University of Ulm, 89081 Ulm, Germany.; Division of Neurodegenerative Disorders, Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translational Neurosciences, Heidelberg University, 61867 Mannheim, Germany., Weishaupt JH; Department of Neurology, University of Ulm, 89081 Ulm, Germany.; Division of Neurodegenerative Disorders, Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translational Neurosciences, Heidelberg University, 61867 Mannheim, Germany.
Jazyk:	angličtina
Zdroj:	Brain communications [Brain Commun] 2020 Aug 21; Vol. 2 (2), pp. fcaa133. Date of Electronic Publication: 2020 Aug 21 (Print Publication: 2020).
DOI:	10.1093/braincomms/fcaa133
Abstrakt:	Loss-of-function mutations in TANK-binding kinase 1 cause genetic amyotrophic lateral sclerosis and frontotemporal dementia. Consistent with incomplete penetrance in humans, haploinsufficiency of TANK-binding kinase 1 did not cause motor symptoms in mice up to 7 months of age in a previous study. Ageing is the strongest risk factor for neurodegenerative diseases. Hypothesizing that age-dependent processes together with haploinsufficiency of TANK-binding kinase 1 could create a double hit situation that may trigger neurodegeneration, we examined mice with hemizygous deletion of Tbk1 ( Tbk1 +/- mice) and wild-type siblings up to 22 months. Compared to 4-month old mice, aged, 22-month old mice showed glial activation, deposition of motoneuronal p62 aggregates, muscular denervation and profound transcriptomic alterations in a set of 800 immune-related genes upon ageing. However, we did not observe differences regarding these measures between aged Tbk1 +/- and wild-type siblings. High age did also not precipitate TAR DNA-binding protein 43 aggregation, neurodegeneration or a neurological phenotype in Tbk1 +/ - mice. In young Tbk1 +/ - mice, however, we found the CNS immune gene expression pattern shifted towards the age-dependent immune system dysregulation observed in old mice. Conclusively, ageing is not sufficient to precipitate an amyotrophic lateral sclerosis or frontotemporal dementia phenotype or spinal or cortical neurodegeneration in a model of Tbk1 haploinsufficiency. We hypothesize that the consequences of Tbk1 haploinsufficiency may be highly context-dependent and require a specific synergistic stress stimulus to be uncovered. (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)
Databáze:	MEDLINE
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