Abstract

C9ORF72, one of the most common genes implicated in amyotrophic lateral sclerosis and frontotemporal dementia, induces neurodegeneration through various pathways. The most notable is interference through liquid-liquid phase separation (LLPS). LLPS is a biophysical phenomenon involved in many fundamental biological processes, such as the formation of membraneless organelles (MLOs), transcription, and nucleocytoplasmic transport. The Arg-rich dipeptide repeat proteins (R-DPRs) produced from the aberrant C9ORF72 gene are highly charged and are incorporated into the phase-separated MLOs, inhibiting their functions. However, the detailed molecular mechanism remains to be elucidated. Recently, we analyzed the structure-function relationship of R-DPRs and clarified the mechanism by which the sticker Arg and the spacer Pro/Gly regulate cytotoxicity and subcellular localization. Natural R-DPRs contribute to the localization of specific MLOs. In this review, we discuss the roles of the sticker and spacer of R-DPRs in the LLPS and how they regulate subcellular localization, protein-protein interaction, and neurotoxicity.

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