Vol. 1 No. 1 (2024)
Articles

Intricate roles of spacers and stickers of Arg-rich C9ORF72 dipeptide repeat proteins; from toxicity to targeting to membraneless organelles

Tamami Miyagi
Tokyo Medical University
Kohsuke Kanekura
Tokyo Medical University
Bio

Published 2023-12-13

Keywords

  • amyotrophic lateral sclerosis (ALS),
  • C9ORF72,
  • membraneless organelle (MLO),
  • Arg-rich dipeptide repeat protein,
  • liquid-liquid phase separation (LLPS)

How to Cite

Miyagi, T., & Kanekura, K. (2023). Intricate roles of spacers and stickers of Arg-rich C9ORF72 dipeptide repeat proteins; from toxicity to targeting to membraneless organelles. Organelle, 1(1). https://doi.org/10.61747/0ifp.202311001

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.

Downloads

Download data is not yet available.