Background:The highly flexible C-terminal region of TDP-43 is implicated in disease pathology. Results: An amyloidogenic core was identified to be critical for TDP-43 aggregation. Conclusion: Helix-to-sheet structural transformation of the amyloidogenic core initiates TDP-43 aggregation and cytoplasmic inclusion formation. Significance: This is a potential therapeutic target for mitigating the TDP-43 proteinopathies.

Edited by Barry HalliwellKeywords: TAR DNA binding protein of 43kDa C-terminal fragment of $35kDa Sequestration Cytoplasmic inclusion RNA recognition motif a b s t r a c t TDP-43 (TAR DNA binding protein of 43kDa) and its C-terminal fragments are thought to be linked to the pathologies of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Here, we demonstrate that the aggregates or inclusions formed by its 35-kDa fragment (namely TDP-35) sequester full-length TDP-43 into cytoplasmic inclusions; and this sequestration is mediated by binding with RNA that is enriched in the cytoplasmic inclusions. RNA recognition motif 1 (RRM1) of TDP-43/TDP-35 plays a dominant role in nucleic-acid binding; mutation in this moiety abrogates formation of the TDP-35 inclusions and its RNA-assisted association with TDP-43. Thus, TDP-35 is able to sequester TDP-43 from nuclear localization into cytoplasmic inclusions, and RNA binding plays an essential role in this process.