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-bound proteins include constituents of non-membrane invested cellular organelles and intermediate filaments. PR targets are enriched for the inclusion of low complexity (LC) sequences. Evidence is presented indicating that LC sequences represent the direct target of PR binding and that interaction between the PR poly-dipeptide and LC domains is polymer-dependent. These studies indicate that PR-mediated toxicity may result from broad impediments to the dynamics of cell structure and information flow from gene to message to protein.