EMBO reportsOct 5, 2026

TBK1 helps remove clumping-prone TDP-43 protein using an immune pathway in ALS models

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Oct 7, 2026

Abstract

Loss-of-function mutations in TBK1 are linked to ALS and FTD through impaired TDP-43 clearance.

A novel proteostatic pathway involving TBK1 and the immunoproteasome regulates the clearance of TDP-43.
TBK1 is activated by aggregated TDP-43, which helps reduce TDP-43 pathology in neuronal cells.
Activation of TBK1 leads to increased expression of IFNβ, enhancing the degradation of TDP-43 in neurons.
Reduced expression of the IFNβ receptor is observed in spinal motor neurons from ALS patients exhibiting TDP-43 pathology.
In SOD1G93A mice, deletion of one Tbk1 gene impairs the induction of the immunoproteasome and increases protein accumulation in the spinal cord.

Simplified

Loss-of-function mutations in TANK-binding kinase 1 (TBK1) cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), characterized by cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43), known as TDP-43 pathology, but the mechanisms beyond impaired autophagy remain undefined. Here, we identify a TBK1-IFNβ-immunoproteasome axis as a novel autophagy-independent proteostatic pathway regulating TDP-43 clearance. TBK1 is activated by aggregation-prone monomeric TDP-43 via physical association, and this activation alleviates TDP-43 pathology in neuronal cells. TBK1 subsequently induces IFNβ expression, which upregulates the immunoproteasome to promote degradation of monomeric TDP-43 in neurons, including human iPSC-derived lower motor neurons. Importantly, IFNβ receptor expression is downregulated in spinal motor neurons from ALS patients with TDP-43 pathology. Furthermore, heterozygous Tbk1 deletion in SOD1^G93A mice impairs immunoproteasome induction and increases polyubiquitinated protein accumulation in spinal cords, supporting the in vivo relevance of this pathway. Collectively, our findings reveal that impairment of the TBK1-IFNβ-immunoproteasome axis represents an autophagy-independent mechanism contributing to the development of TDP-43 pathology in ALS and FTD.

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TBK1 helps remove clumping-prone TDP-43 protein using an immune pathway in ALS models

Abstract

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