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

h-31ca9240f9fc

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

Elo ratings (across arenas)

Arena	Rating	RD	W-L-D	N
als	1996	±168	8-0-0	8
global	1467	±247	1-1-0	2

Ancestry (oldest → this)

(no parents — root hypothesis)

Descendants

mutate TBK1 Deficiency Disrupts Microglial Metabolic Reprogramming, Promoting Glycolyti

1250 (4 matches)

crossover TBK1 Loss Drives MMP-9-Mediated TDP-43 Fragmentation Through Senescent Microglia

1339 (4 matches)

mutate TBK1 Loss Drives Motor Neuron Death Through Impaired Mitophagy and Metabolic Col

1598 (4 matches)

crossover TBK1 Loss Drives Microglial Senescence-SASP to Generate MMP-9-Mediated TDP-43 C-

1079 (4 matches)

mutate TBK1 Loss Triggers Astrocyte-to-Neuron Senescence Propagation Through SASP-Media

1500 (0 matches)

crossover TBK1 Loss Triggers eIF2α-Mediated Translational Repression Through Microglial SA

1500 (0 matches)