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

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

PROVIDER: PRJNA1069041 | ENA |

REPOSITORIES: ENA

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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]

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.

2025-07-09 | GSE254227 | GEO

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

2025-07-09 | GSE290810 | GEO

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

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.

2024-03-19 | PXD050731 | Pride

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

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

| PRJNA1069042 | ENA

Phospho-proteome profiling in human neurons reveals targets of TBK1 in ALS/FTD-Phospho-proteome profiling in human neurons reveals targets of TBK1 in ALS/FTD-associated autophagy networks

Project description:Loss-of-function variants in TBK1, encoding a serine/threonine protein kinase, are strongly associated with sporadic and familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the targets of TBK1 in neurons are unknown, and how haploinsufficiency for TBK1 leads to age-related neurodegeneration remains unresolved. Here, we utilized sets of isogenic induced pluripotent stem cells (iiPSCs) with loss of TBK1 or loss of optineurin (OPTN) for quantitative proteomics and phospho-proteomics across tens of thousands of phospho-sites in proliferating stem cells and induced excitatory neurons. We found that TBK1 sustains the abundance and phosphorylation of its interacting adapter proteins, AZI2/NAP1, TBKBP1, and TANK1, in the cellular context of neurons. Moreover, TBK1 regulates the phosphorylation of selective autophagy proteins, particularly at novel phospho-serine residues within cargo receptors, and endo-lysosomal pathways, including the late-endosome GTPase RAB7A, in human neurons. Additionally, we observed that the disease-associated TBK1 G217R variant acts as a phospho-protein quantitative trait locus (ppQTL) for the phosphorylation status of familial ALS-associated proteins p62/SQSTM1 and OPTN, as well as GABARAPL2, an Atg8- family autophagy protein. Furthermore, we demonstrate that TBK1 is required for neurite outgrowth and lysosomal function. Finally, we provide a census of the phospho-proteome in nascent human neurons for further dissection of protein phosphorylation in neural-enriched proteins, such as tau, in neurological and psychiatric disorders. These studies provide a global view of TBK1 as a central point of convergence in ALS/FTD-linked endo-lysosomal networks that act in a cell-autonomous manner to maintain protein homeostasis in neurons.

2025-09-30 | GSE308151 | GEO

Phospho-proteome profiling in human neurons reveals targets of TBK1 in ALS/FTD-Phospho-proteome profiling in human neurons reveals targets of TBK1 in ALS/FTD-associated autophagy networks [iNeurons]

2025-09-30 | GSE308008 | GEO

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

| PRJNA1230156 | ENA

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

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

| PRJNA1069032 | ENA

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