TBK1 Loss Triggers Astrocyte-to-Neuron Senescence Propagation Through SASP-Mediated Paracrine Signaling in ALS

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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 signatu