Toxic PR Poly-Dipeptides Encoded by the C9orf72 Repeat Expansion Target LC Domain Polymers

Two complementary approaches were used in search of the intracellular targets of the toxic PR poly-dipeptide encoded by the repeat sequences expanded in the C9orf72 form of amyotrophic lateral sclerosis. The top categories of PR_n-bound proteins include constituents of non-membrane invested cellular organelles and intermediate filaments. PR_n targets are enriched for the inclusion of low complexity (LC) sequences. Evidence is presented indicating that LC sequences represent the direct target of PR_n binding and that interaction between the PR_n poly-dipeptide and LC domains is polymer-dependent. These studies indicate that PR_n-mediated toxicity may result from broad impediments to the dynamics of cell structure and information flow from gene to message to protein.