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

## TL;DR

This paper explores how mutations in the TBK1 gene contribute to ALS and FTD by impairing autophagy and protein regulation.

## Contribution

The paper provides mechanistic insights into how different TBK1 mutations disrupt autophagy in neurodegenerative diseases.

## Key findings

- TBK1 mutations impair autophagy by disrupting cargo recognition and autophagosome formation.
- Truncating TBK1 mutations lead to haploinsufficiency, while missense mutations affect specific domains.
- TBK1 dysfunction contributes to proteostatic failure in ALS and FTD.

## Abstract

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.