TBK1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia: Mechanistic Insights into Impaired Autophagy and Proteostatic Failure

Mutations in the TANK-binding kinase 1 (TBK1) gene represent a significant genetic link across the Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) spectrum. As a multifunctional serine/threonine kinase, TBK1 serves as a central orchestrator of the autophagy-lysosome pathway, regulating critical stages from initial cargo recognition and autophagosome biogenesis to vesicle maturation and lysosomal fusion. This review examines the mechanisms by which TBK1 coordinates these diverse autophagic functions. We then focus on how ALS/FTD-associated mutations-ranging from truncating variants causing haploinsufficiency to domain-specific missense mutations-disrupt these essential processes.