ALS Mutations Disrupt Phase Separation Mediated by -Helical Structure in the TDP-43 Low-Complexity C-Terminal Domain. Conference Paper uri icon


  • RNA-binding protein TDP-43 mediates essential RNA processing but forms cytoplasmic neuronal inclusions via its C-terminal domain (CTD) in amyotrophic lateral sclerosis (ALS). It remains unclear if aggregated TDP-43 is neurotoxic and if 50 ALS-associated missense mutations in TDP-43 CTD promote aggregation, or if loss of normal function plays a role in disease. Recent work points to the ability of related proteins to assemble into functional phase-separated ribonucleoprotein granules via their structurally disordered prion-like domains. Here, we provide atomic details on the structure and assembly of the low-complexity CTD of TDP-43 into liquid-liquid phase-separated invitro granules and demonstrate that ALS-associated variants disrupt interactions within granules. Using nuclear magnetic resonance spectroscopy, simulation, and microscopy, we findthat a subregion cooperatively but transiently foldsinto a helix that mediates TDP-43 phase separation. ALS-associated mutations disrupt phase separation by inhibiting interaction and helical stabilization. Therefore, ALS-associated mutations can disrupt TDP-43 interactions, affecting function beyond encouraging aggregation.

published proceedings

  • Structure

altmetric score

  • 91.28

author list (cited authors)

  • Conicella, A. E., Zerze, G. H., Mittal, J., & Fawzi, N. L.

citation count

  • 458

complete list of authors

  • Conicella, Alexander E||Zerze, Gül H||Mittal, Jeetain||Fawzi, Nicolas L

publication date

  • September 2016