The Loss of TBK1 Kinase Activity in Motor Neurons or in All Cell Types Differentially Impacts ALS Disease Progression in SOD1 Mice

Gerbino, Valeria; Kaunga, Esther; Ye, Junqiang; Canzio, Daniele; O’Keeffe, Sean; Rudnick, Noam D.; Guarnieri, Paolo; Lutz, Cathleen; Maniatis, Tom

doi:10.1016/j.neuron.2020.03.005

Cited by 78 publications

(70 citation statements)

References 70 publications

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“…It was recently noted that glial activation differs between ALS models. In contrast to extensive activation in SOD1 models, mouse models carrying patient-derived mutations or haploinsufficiency of TANK-binding kinase 1 (TBK1) and optineurin (encoded by OPTN gene) lack overt microgliosis and astrocytosis ( Ito et al , 2016 ; Gerbino et al , 2020 ). Similarly, in a model in which TDP-43 pathology can be reversibly induced in neurons, microglia are only subtly activated ( Spiller et al , 2018 ).…”

Section: Glial Cells As Key Contributors To Als Pathogenesismentioning

confidence: 99%

“…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.…”

Section: How Does Immunity Turn From Friend To Foe During Als?mentioning

confidence: 99%

“…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 ).…”

Section: How Does Immunity Turn From Friend To Foe During Als?mentioning

confidence: 99%

“…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.…”

Section: How Does Immunity Turn From Friend To Foe During Als?mentioning

confidence: 99%

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

Béland

Markovinović

Jakovac

et al. 2020

Brain Communications

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Despite wide genetic, environmental and clinical heterogeneity in amyotrophic lateral sclerosis, a rapidly fatal neurodegenerative disease targeting motoneurons, neuroinflammation is a common finding. It is marked by local glial activation, T cell infiltration and systemic immune system activation. The immune system has a prominent role in the pathogenesis of various chronic diseases, hence some of them, including some types of cancer, are successfully targeted by immunotherapeutic approaches. However, various anti-inflammatory or immunosuppressive therapies in amyotrophic lateral sclerosis have failed. This prompted increased scrutiny over the immune-mediated processes underlying amyotrophic lateral sclerosis. Perhaps the biggest conundrum is that amyotrophic lateral sclerosis pathogenesis exhibits features of three otherwise distinct immune dysfunctions –excessive inflammation, autoimmunity and inefficient immune responses. Epidemiological and genome-wide association studies show only minimal overlap between amyotrophic lateral sclerosis and autoimmune diseases, so excessive inflammation is usually thought to be secondary to protein aggregation, mitochondrial damage or other stresses. In contrast, several recently characterized amyotrophic lateral sclerosis-linked mutations, including those in TBK1, OPTN, CYLD and C9orf72, could lead to inefficient immune responses and/or damage pile-up, suggesting that an innate immunodeficiency may also be a trigger and/or modifier of this disease. In such cases, nonselective immunosuppression would further restrict neuroprotective immune responses. Here we discuss multiple layers of immune-mediated neuroprotection and neurotoxicity in amyotrophic lateral sclerosis. Particular focus is placed on individual patient mutations that directly or indirectly affect the immune system, and the mechanisms by which these mutations influence disease progression. The topic of immunity in amyotrophic lateral sclerosis is timely and relevant, because it is one of the few common and potentially malleable denominators in this heterogenous disease. Importantly, amyotrophic lateral sclerosis progression has recently been intricately linked to patient T cell and monocyte profiles, as well as polymorphisms in cytokine and chemokine receptors. For this reason, precise patient stratification based on immunophenotyping will be crucial for efficient therapies.

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Section: Glial Cells As Key Contributors To Als Pathogenesismentioning

confidence: 99%

Section: How Does Immunity Turn From Friend To Foe During Als?mentioning

confidence: 99%

Section: How Does Immunity Turn From Friend To Foe During Als?mentioning

confidence: 99%

Section: How Does Immunity Turn From Friend To Foe During Als?mentioning

confidence: 99%

See 2 more Smart Citations

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

Béland

Markovinović

Jakovac

et al. 2020

Brain Communications

View full text Add to dashboard Cite

show abstract

“…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.…”

Section: Discussionmentioning

confidence: 99%

TBK1 interacts with tau and enhances neurodegeneration in tauopathy

Abreha

Ojelade

Dammer

et al. 2020

Preprint

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Running title: TBK1 is a tau-directed kinase Key words: TANK-binding kinase 1 (TBK1), microtubule associated protein tau (MAPT), neurofibrillary tangles (NFTs), Alzheimer's disease (AD), familial frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), co-immunoprecipitation (co-IP), mass spectrometry (MS), post-translational modification (PTM), Drosophila, IκB kinase (IKK) ABSTRACT One of the defining pathological features of Alzheimer's Disease (AD) is the deposition of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau in the brain. Aberrant activation of kinases in AD has been suggested to enhance phosphorylation and toxicity of tau, making the responsible taudirected kinases attractive therapeutic targets. The full complement of tau interacting kinases in AD brain and their activity in disease remains incompletely defined.Here, immunoaffinity enrichment coupled with mass spectrometry (MS) identified TANKbinding kinase 1 (TBK1) as a tau-interacting partner in human AD cortical brain tissues. We validated this interaction in both human AD and familial frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) caused by mutations in MAPT (R406W) postmortem brain tissues as well as human cell lines. Further, we document increased TBK1 activity in both AD and FTDP-17 and map the predominant TBK1 phosphorylation sites on tau based on in vitro kinase assays coupled to MS. Lastly, in a Drosophila tauopathy model, activating expression of a conserved TBK1 ortholog triggers tau hyperphosphorylation and enhanced neurodegeneration, whereas knockdown had the reciprocal effect, suppressing tau toxicity. Collectively, our findings suggest that increased TBK1 activity may promote tau hyperphosphorylation and neuronal loss in AD and related tauopathies.

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Loss‐of‐function variants in RNA binding motif protein X‐linked induce neuronal defects contributing to amyotrophic lateral sclerosis pathogenesis

He,

Shen

et al. 2024

MedComm

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Despite being one of the most prevalent RNA modifications, the role of N6‐methyladenosine (m6A) in amyotrophic lateral sclerosis (ALS) remains ambiguous. In this investigation, we explore the contribution of genetic defects of m6A‐related genes to ALS pathogenesis. We scrutinized the mutation landscape of m6A genes through a comprehensive analysis of whole‐exome sequencing cohorts, encompassing 508 ALS patients and 1660 population‐matched controls. Our findings reveal a noteworthy enrichment of RNA binding motif protein X‐linked (RBMX) variants among ALS patients, with a significant correlation between pathogenic m6A variants and adverse clinical outcomes. Furthermore, Rbmx knockdown in NSC‐34 cells overexpressing mutant TDP43Q331K results in cell death mediated by an augmented p53 response. Similarly, RBMX knockdown in ALS motor neurons derived from induced pluripotent stem cells (iPSCs) manifests morphological defects and activation of the p53 pathway. Transcriptional analysis using publicly available single‐cell sequencing data from the primary motor cortex indicates that RBMX‐regulated genes selectively influence excitatory neurons and exhibit enrichment in ALS‐implicated pathways. Through integrated analyses, our study underscores the emerging roles played by RBMX in ALS, suggesting a potential nexus between the disease and dysregulated m6A‐mediated mRNA metabolism.

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The Loss of TBK1 Kinase Activity in Motor Neurons or in All Cell Types Differentially Impacts ALS Disease Progression in SOD1 Mice

Cited by 78 publications

References 70 publications

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

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

TBK1 interacts with tau and enhances neurodegeneration in tauopathy

Loss‐of‐function variants in RNA binding motif protein X‐linked induce neuronal defects contributing to amyotrophic lateral sclerosis pathogenesis

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