This hypothesis proposes that TBK1 loss-of-function mutations drive ALS pathogenesis by inducing senescence in astrocytes, which then propagate senescent signals to motor neurons through SASP-mediated paracrine mechanisms, ultimately causing neuronal dysfunction and death. Supporting evidence includes the 2025 Nat Commun study showing that TBK1 deletion creates an aged-like transcriptional signature with increased inflammatory gene expression, suggesting cellular senescence induction. The Cell (2018) work demonstrating that TBK1 insufficiency unleashes RIPK1-driven inflammation supports astrocyte senescence as a plausible upstream trigger. Astrocyte-specific mechanisms are supported by evidence that these cells are particularly vulnerable to autophagy dysfunction and can undergo senescence in response to proteostatic stress. The paracrine propagation model is strengthened by research showing that senescent astrocytes secrete pro-inflammatory cytokines (IL-6, TNF-α, IL-1β) and damage-associated molecular patterns that can induce secondary senescence in neighboring cells.

This hypothesis proposes that TBK1 loss-of-function mutations drive ALS pathogenesis by inducing senescence in astrocytes, which then propagate senescent signals to motor neurons through SASP-mediated paracrine mechanisms, ultimately causing neuronal dysfunction and death. Supporting evidence includes the 2025 Nat Commun study showing that TBK1 deletion creates an aged-like transcriptional signature with increased inflammatory gene expression, suggesting cellular senescence induction. The Cell (2018) work demonstrating that TBK1 insufficiency unleashes RIPK1-driven inflammation supports astrocyte senescence as a plausible upstream trigger. Astrocyte-specific mechanisms are supported by evidence that these cells are particularly vulnerable to autophagy dysfunction and can undergo senescence in response to proteostatic stress. The paracrine propagation model is strengthened by research showing that senescent astrocytes secrete pro-inflammatory cytokines (IL-6, TNF-α, IL-1β) and damage-associated molecular patterns that can induce secondary senescence in neighboring cells. The Cell (2020) finding that TDP-43 pathology activates cGAS-STING signaling provides a mechanistic link between astrocyte SASP and neuronal TDP-43 aggregation. However, the Manganelli et al. review (Cells 2026) challenges this by emphasizing autophagy receptor dysfunction as the primary mechanism, potentially undermining astrocyte-centric senescence models. The Smeyers et al. phospho-proteome data (Cell Rep 2025) showing predominantly neuronal TBK1 substrates suggests cell-autonomous neuronal dysfunction rather than astrocyte-mediated pathology. Additionally, direct evidence for astrocyte senescence propagation in ALS models remains limited, and whether SASP factors can effectively induce motor neuron senescence requires experimental validation. While astrocyte dysfunction is well-established in ALS, the specific role of TBK1-induced astrocyte senescence as a disease driver versus consequence remains to be definitively established.