TBK1 eliminates aggregation-prone monomeric TDP-43 through an IFNβ-immunoproteasome pathway in ALS models

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Abstract
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.
Funding Information
  • Japan Society for the Promotion of Science (JP22J23468)
  • Japan Society for the Promotion of Science (JP25K23745)
  • Japan Society for the Promotion of Science (JP18H02740)
  • Japan Society for the Promotion of Science (JP19KK0214)
  • Japan Society for the Promotion of Science (JP22H00467)
  • Japan Agency for Medical Research and Development (JP22ek0109426)
  • Japan Agency for Medical Research and Development (JP24wm0425014)
  • Japan Agency for Medical Research and Development (JP26wm0625301)
  • THE YUKIHIKO MIYATA MEMORIAL TRUST FOR ALS RESEARCH (n/a)
  • IKEDA RIKA Grant (n/a)
  • Wellcome Trust (221824/Z/20/Z)
  • Motor Neurone Disease Association (Sreedharan/Apr24/2362-791)

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