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

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.

The Overlapping Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

“…Heterozygous deletion of the α-IFN receptor Ifnar1 significantly prolongs the life span of SOD1G93A ALS mice (Wang et al, 2011). In a 2019 study, Brenner et al (2019) further elucidated on the connection between TBK1 and SOD1 in the mouse models. The group showed that at the early stage, heterozygous Tbk1 deletion impairs autophagy in motoneurons and prepones the clinical onset and muscular denervation in SOD1G93A/Tbk1 ± mice, while at the late disease stage, it significantly alleviates microglial neuroinflammation, decelerates disease progression, and extends mouse survival (Brenner et al, 2019).…”

Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses

“…In ALS patients bearing a TBK1 mutation, it was suggested that the TBK1-induced pathology was caused by a loss of function from haploinsufficiency as TBK1 mRNA and protein levels were reduced in comparison to sporadic ALS patients ( Freischmidt et al , 2015 ; Pottier et al , 2015 ). In mice, TBK1 deficiency is lethal, whereas haploinsufficiency is insufficient to cause the disease by itself ( Brenner et al , 2019 ; Gerbino et al , 2020 ). However, in a mutant hSOD1 model, haploinsufficiency of TBK1 or a loss-of-function mutation in TBK1 R228H showed a biphasic effect on the disease course: accelerating disease onset, but afterwards suppressing the appearance of neurotoxic microgliosis and astrogliosis, and extending survival.…”

“…However, in a mutant hSOD1 model, haploinsufficiency of TBK1 or a loss-of-function mutation in TBK1 R228H showed a biphasic effect on the disease course: accelerating disease onset, but afterwards suppressing the appearance of neurotoxic microgliosis and astrogliosis, and extending survival. Primary microglia from TBK1 +/− SOD1 G93A mice exhibited diminished production of proinflammatory cytokines in vitro ( Brenner et al , 2019 ). TBK1 R228H SOD1 G93A mice led to diminished IRF3 activation and decreased induction of IFN-stimulated genes at the late stage of the disease.…”

“…It was thus proposed that diminished inflammatory responses due to TBK1 insufficiency slow down the disease progression at late stages ( Gerbino et al , 2020 ). Given that TBK1 also has a role in promoting autophagy, the authors proposed that the accelerated early-stage disease in TBK1 +/− mutant hSOD1 ALS model resulted from defective autophagy ( Brenner et al , 2019 ; Gerbino et al , 2020 ). However, this does not exclude the possibility that innate immunodeficiency resulting from diminished IFN-β production could contribute as well.…”

TBK1 interacts with tau and enhances neurodegeneration in tauopathy

“…Moreover, in mouse brain, TBK1 suppresses RIPK1 activation and downstream neuroinflammation associated with a loss of function phenotype in ALS/FTD (70). Notably, the TBK1 haploinsufficiency phenotype associated with ALS/FTD aggravates autophagy defects and early onset of motor defects, while TBK1 haploinsufficiency at later stages seems to alleviate neuroinflammation and slow disease progression in mice models (71,72). Thus, we recognize that TBK1 likely has key roles in glia and that cell type-specific phenotypes will likely differ upon global inhibition of TBK1 depending on the brain region and disease stage.…”