Atomic structures of TDP-43 LCD segments and insights into reversible or pathogenic aggregation.

Abstract

The normally soluble TAR DNA Binding Protein 43 (TDP-43) is found aggregated both in reversible stress granules and irreversible pathogenic amyloid. In TDP-43, the low complexity domain (LCD) is believed to be involved in both types of aggregation. To discover the structural origins of these two modes of β-sheet rich aggregation, we have determined ten structures of segments of the LCD of human TDP-43. Six of these segments form steric zippers characteristic of the spines of pathogenic amyloid fibrils; four others form LARKS, the labile amyloid-like interactions characteristic of protein hydrogels and proteins found in membrane-less organelles, including stress granules. Supporting a hypothetical pathway from reversible to irreversible amyloid aggregation, we found that familial ALS variants of TDP-43 convert LARKS to irreversible aggregates. Our structures suggest how TDP-43 adopts both reversible and irreversible β-sheet aggregates, and the role of mutation in the possible transition of reversible to irreversible pathogenic aggregation.