| TBK1 — TANK Binding Kinase 1 | |
|---|---|
| Symbol | TBK1 |
| Full Name | TANK Binding Kinase 1 |
| Chromosome | 12q14.2 |
| NCBI Gene | 29110 |
| Ensembl | ENSG00000183735 |
| OMIM | 604834 |
| UniProt | Q9UHD2 |
| Diseases | ALS, FTD |
| Expression | Motor cortex, Spinal cord, Immune cells |
| Key Mutations | |
| Loss-of-function mutations E696K I397T R357X |
|
Tbk1 — Tank Binding Kinase 1 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
TBK1 (TANK Binding Kinase 1) is a serine/threonine kinase gene located on chromosome 12q14.2 that encodes a key enzyme at the crossroads of innate immunity and selective autophagy. Dominant loss-of-function mutations in TBK1 were identified as a significant genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in 2015 through independent studies (Cirulli et al., 2015; Freischmidt et al., 2015). TBK1 mutations represent the third most frequent genetic cause of FTD in some populations (after C9orf72 and GRN), and the second most common cause of familial ALS after C9orf72 (Gijselinck et al., 2015). The gene is catalogued as NCBI Gene ID 29110 and OMIM 604834.
TBK1 belongs to the IκB kinase (IKK) subfamily of kinases, originally characterized for its role in activating innate immune signaling through the induction of type I interferons in response to viral infection. The protein contains a kinase domain (KD), a ubiquitin-like domain (ULD), and a scaffold/dimerization domain (SDD) (Ahmad et al., 2016).
TBK1 plays a critical role in selective autophagy—the targeted degradation of damaged organelles and protein aggregates. TBK1 phosphorylates autophagy receptors optineurin (OPTN), p62/SQSTM1, NDP52 (CALCOCO2), and TAX1BP1, which bridge ubiquitinated cargo to autophagic membranes (Richter et al., 2016). Specifically:
TBK1 is a critical inducer of type I interferons, activated downstream of pattern recognition receptors including cGAS-STING and RIG-I-like receptors. Notably, TBK1 activated during autophagy does not cross-activate innate immunity signaling targets, suggesting pathway-specific regulation (Ahmad et al., 2016).
In the PINK1–Parkin mitophagy pathway, TBK1 is recruited to ubiquitinated damaged mitochondria where it phosphorylates OPTN and NDP52 to promote mitophagic clearance (Lazarou et al., 2015).
TBK1 is expressed in the motor cortex, spinal cord, and ubiquitously in immune cells—particularly microglia, where its loss shifts cells toward an aged-like phenotype (Bhargava et al., 2025). Expression data is available from the Allen Human Brain Atlas.
TBK1 mutations are linked to the following neurodegenerative conditions:
| Mutation | Type | Effect |
|---|---|---|
| E696K | Missense | Causes autophagolysosomal dysfunction in motor neurons, progressive motor neuron disease in mouse knock-in models (Bhatti et al., 2024) |
| I397T | Missense | Disrupts mitophagy and accumulates damaged mitochondria |
| R357X | Nonsense | Truncation causing haploinsufficiency |
| Various LOF | Frameshift/splice | Complete loss of one functional allele |
ALS-associated missense mutations in TBK1 differentially disrupt mitophagy, with some mutations inhibiting or delaying clearance of damaged organelles, leading to accumulation of dysfunctional mitochondria that may produce cytotoxic reactive oxygen species (ROS) (Harding et al., 2021).
TBK1-related ALS/FTD presents potential therapeutic targets:
The study of Tbk1 — Tank Binding Kinase 1 has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
Page expanded by NeuroWiki quality review. Last updated: 2026-02-27.