TBK1 Loss Locks Microglia in an Aged/Senescent Transcriptional State, Fueling ALS-Associated SASP

The hypothesis proposes that loss-of-function mutations in TBK1 contribute to ALS pathogenesis by trapping microglia in a senescent, pro-inflammatory state characterized by the Senescence-Associated Secretory Phenotype (SASP), thereby accelerating disease progression. Supporting evidence includes a 2025 Nat Commun study demonstrating that microglia-specific TBK1 deletion in an ALS/FTD mouse model reproduces an aged-like transcriptional signature with increased inflammatory gene expression. Complementary work published in Cell (2018) established that partial TBK1 insufficiency during aging unleashes RIPK1-driven inflammation, linking TBK1 haploinsufficiency to age-dependent neurodegeneration. Human genetic evidence further supports this axis: TBK1 haploinsufficiency is recognized as a causal familial ALS/FTD risk mechanism. Additionally, research published in Cell (2020) showed that TDP-43 pathology can activate cGAS-STING signaling in ALS, implicating the innate immune pathway downstream of TBK1 loss. However, contradictory evidence exists. A comprehensive review (Manganelli et al., Cells 2026) found that TBK1 loss primarily impairs autophagy receptor phosphorylation (p62/OPTN/NDP52) and proteostasis, with senescence-SASP proposed as only one of several pathways lacking direct in vivo validation. Phospho-proteome profiling in human neurons (Smeyers et al., Cell Rep 2025) revealed that ALS/FTD-associated TBK1 substrates are predominantly neuronal proteins (FIP200, OPTN, p62) rather than microglial senescence effectors, suggesting the primary TBK1 pathogenic mechanism operates in neurons rather than through microglial SASP signaling. Thus, while the microglial aging axis remains plausible and is supported by animal models, the prevailing mechanistic evidence points toward neuronal autophagy dysfunction as the dominant pathway, with microglial senescence possibly representing a secondary or contributing phenomenon.