Identifying and characterizing effectors of low complexity protein domain assembly

TDP-43 is an RNA and DNA processing protein with a highly conserved, C-terminal low-complexity domain. In vitro, the TDP-43 low complexity domain can form liquid-liquid phase separations which readily mature into amyloid fibrils. Fibrils containing C-terminal fragments of TDP-43 have been identified within cellular inclusions of post-mortem neuronal tissue in a considerable range of neurodegenerative diseases, including ALS, FTD, and Alzheimer’s. Nearly all ALS-associated mutations are found in the low complexity domain, further highlighting its significance to disease.