Haploinsufficiency of TANK-binding kinase 1 prepones age-associated neuroinflammatory changes without causing motor neuron degeneration in aged mice - Sorbonne Université
Journal Articles Brain Communications Year : 2020

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

Abstract

Abstract 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.
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hal-04519695 , version 1 (25-03-2024)

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Clara Bruno, Kirsten Sieverding, Axel Freischmidt, Takashi Satoh, Paul Walther, et al.. Haploinsufficiency of TANK-binding kinase 1 prepones age-associated neuroinflammatory changes without causing motor neuron degeneration in aged mice. Brain Communications, 2020, 2 (2), pp.fcaa133. ⟨10.1093/braincomms/fcaa133⟩. ⟨hal-04519695⟩
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