Human TBK1: A Gatekeeper of Neuroinflammation

The importance of TANK binding kinase-1 (TBK1), a multimeric kinase that modulates inflammation and autophagy, in human health has been highlighted for the first time by the recent discoveries of mutations in TBK1 that underlie amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), normal tension glaucoma (NTG) or childhood herpes simplex encephalitis (HSE). Gain-of-function of TBK1 are associated with NTG, whereas loss-of-function mutations result in ALS/FTD or in HSE. In light of these new findings, we review the role of TBK1 in these seemingly unrelated, yet allelic diseases, and discuss the role of TBK1 in neuroinflammatory diseases. This discovery has the potential to significantly increase our understanding of the molecular basis of these poorly understood diseases.

TrendsHSE, in a subset of children, is caused by impaired antiviral interferon (IFN) production due to monogenic mutations in the toll-like receptor 3 (TLR3)–IFN signaling pathway, including mutations in TBK1.Due to advances in sequencing technologies, several new amyotrophic lateral sclerosis (ALS) or ALS–frontotemporal dementia (ALS-FTD) genes have been identified, five of which are known to be involved in autophagy (SQSTM1, VCP, OPTN, UBQLN2, and TBK1). These mutations are thought to contribute to disease pathogenesis, possibly due to impaired autophagy.The genetic etiology of normal tension glaucoma (NTG) has recently been attributed to copy number variants (CNVs) found in chromosome region 12q14, specifically leading to duplications of the TBK1 gene. This duplication has been found to increase TBK1 transcript levels, suggesting a gain-of-function role for TBK1 in NTG.Recent developments in the field of selective autophagy have implicated this evolutionarily conserved process in innate immunity and pathogen clearance, including in neuronal cells.