The multifaceted role of TBK1 as a master regulator of proteostasis and inflammatory pathways is discussed, its critical role in maintaining microglial homeostasis is highlighted, and how these convergent functions inform therapeutic strategies for ALS/FTD is explored.
Abstract
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) comprise a neurodegenerative disease spectrum characterized by TDP-43 pathology and overlapping genetic risk factors. Loss-of-function variants in
TBK1
(TANK-binding kinase 1) represent one of the most common genetic causes of ALS/FTD, highlighting haploinsufficiency for TBK1 as a major contributor to disease pathogenesis. Emerging evidence from iPSC and mouse models suggests that reduced TBK1 activity disrupts interconnected autophagy, endo-lysosomal, and innate immune pathways through both cell-autonomous and non-cell-autonomous mechanisms. In this review, we discuss the multifaceted role of TBK1 as a master regulator of proteostasis and inflammatory pathways, highlight its critical role in maintaining microglial homeostasis, and explore how these convergent functions inform therapeutic strategies for ALS/FTD.
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