TRAF6 regulates ubiquitination-independent TDP-43 condensation and related neurodegeneration

Cytoplasmic aggregates of TDP-43 are hallmarks of multiple neurodegenerative diseases. However, the underlying mechanisms driving TDP-43 pathological aggregation remain elusive. In this study, we revealed that TNF receptor-associated factor 6 (TRAF6) promotes TDP-43 condensation, and disrupting TRAF6-TDP-43 interactions effectively suppresses its aggregation. Our findings reveal that TRAF6 expression increases during senescence and preferentially interacts with RNA-binding-deficient TDP-43, a variant associated with neurotoxicity. Importantly, TRAF6 facilitates TDP-43 aggregation through a mechanism independent of its E3 ligase activity. Furthermore, we identified the motif of TDP-43 responsible for its interaction with TRAF6, enabling the design of a peptide inhibitor. This peptide effectively reduces pathological TDP-43 aggregation in cells and alleviates movement disorders and cognitive decline in mouse models. Together, these results establish a direct link between TRAF6 and TDP-43 neurotoxicity, emphasizing TRAF6’s role in driving TDP-43 pathology, and position TRAF6 as a promising target for combating TDP-43-related neurodegenerative diseases.