Deciphering the Amyloid Foldome of TDP-43

TDP-43 is an essential regulator of RNA splicing and metabolism and its aggregates play key roles in devastating diseases, including Amyotrophic Lateral Sclerosis (ALS)1, Frontotemporal Dementia (FTD) and Limbic-Predominant Age-Related TDP-43 Encephalopathy (LATE)2. Besides this pathological aggregation, TDP-43s oligomerization also serves vital functions3, which adds urgency to determine pathological conformations of TDP-43. The recently published cryo-EM study by Cao, Eisenberg and coworkers now reveals amyloid structures of putative pathological aggregates from TDP-43s C-terminal region4. Whereas the Cao et al.s cryo-EM structures contain both the hydrophobic and Q/N-rich segments, the data were interpreted mainly through the lens of hydrophobic contacts. However, the Q/N-rich region can form amyloid on its own5,6 and therefore additional considerations of the Q/N-rich segments contributions will advance our understanding of TDP-43 aggregation.