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ABSTRACT: Novel Intronic Mutations in TBK1

PROVIDER: PRJNA750742 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15300975_1.fastq.gz	Fastqsanger.gz
	SRR15300975_2.fastq.gz	Fastqsanger.gz
	SRR15300976_1.fastq.gz	Fastqsanger.gz
	SRR15300976_2.fastq.gz	Fastqsanger.gz
	SRR15300977_1.fastq.gz	Fastqsanger.gz

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Project description:Novel Intronic Mutations of TBK1 Promote Aberrant Splicing Modes in Amyotrophic Lateral Sclerosis

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ALS/FTD-linked TBK1 deficiency in microglia induces an aged-like microglial signature and drives social recognition deficits [FACS_SpinalCord_Microglia & LPS_Brain_SpinalCord]

Project description:TANK-Binding Kinase 1 (TBK1) is involved in autophagy and immune signaling. Dominant loss-of-function mutations in TBK1 are linked to Amyotrophic Lateral Sclerosis (ALS), Fronto-temporal dementia (FTD) and ALS/FTD. However, pathogenic mechanisms remain unclear, particularly the cell-type specific disease contributions of TBK1 mutations. Here, we focus on cell-specific Tbk1 deletion in motor neurons or microglia. We find that deleting Tbk1 from mouse motor neurons does not induce transcriptional stress, despite lifelong signs of autophagy deregulations. Conversely, Tbk1 deletion in microglia alters their homeostasis and reactive responses. In both spinal cord and brain, Tbk1 deletion leads to a pro-inflammatory, primed microglial signature with features of ageing and neurodegeneration. While it does not induce or modify ALS-like motor neuron damage, microglial Tbk1 deletion causes early FTD-like social recognition deficits. This phenotype is linked to focal microglial activation and T cell infiltration in the substantia nigra pars reticulata and pallidum. Our results reveal that part of TBK1-linked FTD disease originates from microglial dysfunction.

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ALS/FTD-linked TBK1 deficiency in microglia induces an aged-like microglial signature and drives social recognition deficits. [FACS_Brain_Microglia]

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ALS/FTD-linked TBK1 deficiency in microglia induces an aged-like microglial signature and drives social recognition deficits. [in vitro_Microglia]

2025-07-09 | GSE254217 | GEO

ALS/FTD-linked TBK1 deficiency in microglia induces an aged-like microglial signature and drives social recognition deficits [Microdissected_Motor Neurons]

2025-07-09 | GSE254228 | GEO

In vitro responses of fibroblasts from patients with TBK1 deficiency after TLR3 dependent and independent stimuli

Project description:We report here two unrelated HSE patients carrying different heterozygous mutations (D50A and G159A) in TBK1, the gene encoding TANK-binding kinase 1, a kinase at the crossroads of multiple IFN-inducing signaling pathways. Both mutant TBK1 alleles are loss-of-function, but through different mechanisms: protein instability (D50A) or a loss of kinase activity (G159A). Both are also associated with an autosomal dominant (AD) trait, but by different mechanisms: haplotype-insufficiency (D50A) or negative dominance (G159A). A defect in poly(I:C)-induced TLR3 responses can be detected in fibroblasts heterozygous for G159A, but not for D50A TBK1. Skin fibroblast cell lines were derived from healthy controls (n=3), patients with deficiencies for TBK1 (n=2), TLR3 (n=2), STAT1 (n=1) and cultured for 2 or 8 hours in the presence of IFNa (105 IU/ml), IL1b (20ng/ml), or poly I:C (25ug/ml) or left unstimulated for the same length of time.

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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

Project description:DNA sequence variants in the TBK1 gene associate with or cause sporadic or familial amyotrophic lateral sclerosis (ALS). Here we show that mice bearing human ALS-associated TBK1 missense loss-of-function mutations, or mice in which the Tbk1 gene is selectively deleted in motor neurons, do not display a neurodegenerative disease phenotype. However, loss of TBK1 function in motor neurons of the SOD1G93A mouse model of ALS impairs autophagy, increases SOD1 aggregation, and accelerates early disease onset without affecting lifespan. By contrast, point mutations that decrease TBK1 kinase activity in all cells also accelerate disease onset but extend the lifespan of SOD1 mice. This difference correlates with the failure to activate high levels of expression of interferon-inducible genes in glia. We conclude that loss of TBK1 kinase activity impacts ALS disease progression through distinct pathways in different spinal cord cell types and further implicate the importance of glia in neurodegeneration.

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TBK1 p.E696K mutation causes autophagolysosomal dysfunction and ALS/FTD-like symptoms in mice

Project description:While deleterious mutations are responsible for the vast majority of TBK1-linked ALS/FTD cases, the ALS/FTD causing missense mutation p.E696K leads to a selective loss of TBK1/optineurin binding. Knock-in of this specific missense mutation causes progressive autophagolysosomal dysfunction and an ALS/FTD-like phenotype in mice, while, as opposed to TBK1 deletion, RIPK/TNF-α-dependent necroptosis or overt inflammation are absent. Our results highlight the role of autophagolysosomal dysfunction as a therapeutic target in TBK1-ALS/FTD.

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Project description:Outcomes in activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) remain poor and new targets for treatment are needed. NF-κB signalling pathways from the B-cell receptor and Toll-like receptors bear mutations and are constitutively active in ABC-DLBCL but inhibitors of the major components of these signalling pathways have not yet entered clinical practice. The IKK related kinases, IKKε/TBK1, have essential roles in innate immunity and regulate aspects of NF-κB signalling and other pathways. TBK1 mRNA expression is associated with clinical outcome and TBK1 and IKKε are variably expressed in human DLBCL.

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In vitro responses of fibroblasts from patients with TBK1 deficiency after TLR3 dependent and independent stimuli

2012-07-30 | GSE38652 | GEO