“Deciphering the amyloid foldome of TDP-43”

ABSTRACT 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-43’s oligomerization also serves vital functions 3 , 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-43’s C-terminal region 4 . 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 own 5,6 and therefore additional considerations of the Q/N-rich segment’s contributions will advance our understanding of TDP-43 aggregation.