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

Loss of TBK1 function impairs the IFNβ-immunoproteasome pathway, leading to TDP-43 aggregation in ALS models, with a 50% reduction in immunoproteasome induction observed in Tbk1 heterozygous mice.

• Why it matters: Understanding mechanisms beyond autophagy is crucial because TDP-43 pathology is a hallmark of ALS and FTD, and mutations in TBK1 are linked to these diseases. This pathway may reveal new therapeutic targets for proteostasis failure.
• What they did: The study examined how TBK1 activation by monomeric TDP-43 induces IFNβ expression, which then upregulates the immunoproteasome to degrade TDP-43, using neuronal cell models, human iPSC-derived motor neurons, and Tbk1 heterozygous SOD1 G93A mice.
• The result: Disruption of this axis results in increased polyubiquitinated proteins and impaired TDP-43 clearance, suggesting that restoring TBK1-IFNβ-immunoproteasome signaling could mitigate TDP-43 pathology in ALS and FTD.