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

TBK1 activates an IFNβ-immunoproteasome pathway that clears aggregation-prone monomeric TDP-43, reducing pathology in ALS models.

• Why it matters: Understanding mechanisms beyond autophagy is crucial because impaired proteostasis contributes to TDP-43 aggregation, a hallmark of ALS and FTD, yet remains poorly understood.
• What they did: The study used cellular and animal models, including human iPSC-derived neurons and Tbk1 heterozygous mice, to investigate how TBK1 activation induces IFNβ expression and immunoproteasome upregulation for TDP-43 clearance.
• The result: Findings demonstrate that this pathway mitigates TDP-43 aggregation, and its impairment—such as reduced IFNβ receptor expression—may promote disease progression, offering new therapeutic insights.