Repeat Problems: Combinatorial Effect of C9orf72‐Derived Dipeptide Repeat Proteins

Abstract

The most common genetic cause of both Amyotrophic Lateral Sclerosis and Frontotemporal Dementia is a microsatellite expansion mutation in the 5′ UTR region of C9orf72. Expansion of the hexanucleotide repeat region of C9orf72 leads to loss of function, RNA foci, and five species of non‐AUG RAN translated dipeptide repeat proteins (GA, GP, GR, PA, & PR). It has been observed that the sense and antisense dipeptide repeat proteins can be translated simultaneously in one cell, however the interplay between the different species has not been heavily investigated. Here we determined that the antisense repeat protein PR is localized to the nucleus, causes cytotoxicity, disrupts nuclear transport, and triggers PERK phosphorylation and p62 puncta accumulation. However, when PR and its sense partner GA were co‐expressed, PR's localization and cytotoxic outputs were significantly altered. In addition, we showed that GA and PR interact through direct binding that leads to structural and morphological changes. We also demonstrate the ability of dipeptide repeat protein species to be released from one cell and taken up by another. Importantly, we demonstrate that co‐expression of distinct DPRs enhances the release of individual peptides. Thus, the combined expression of distinct C9orf72 derived dipeptide repeat species produces cellular outcomes and structural differences that are unique compared to the expression of a single species.Support or Funding InformationNot fundedThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.