Publication

Phase Separation of Toxic Dipeptide Repeat Proteins Related to C9orf72 ALS/FTD

Jafarinia, H., van der Giessen, E. & Onck, P. R., 18-Aug-2020, In : Biophysical Journal. 119, 4, p. 843-851 9 p.

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  • Phase Separation of Toxic Dipeptide Repeat Proteins Related to C9orf72 ALS/FTD

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DOI

The expansion mutation in the C9orf72 gene is the most common known genetic cause for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This mutation can produce five dipeptide repeat proteins (DPRs), of which three are known to be toxic: poly-PR, poly-GR, and poly-GA. The toxicity of poly-GA is attributed to its aggregation in the cytoplasm, whereas for poly-PR and poly-GR, several toxicity pathways have been proposed. The toxicity of the DPRs has been shown to depend on their length, but the underlying molecular mechanism of this length dependence is not well understood. To address the possible role of phase separation in DPR toxicity, a one-bead-per-amino-acid (1 BPA) coarse-grained molecular dynamics model is used to study the single-molecule and phase-separation properties of the DPRs. We find a strong dependence of the phase-separation behavior on both DPR length and concentration, with longer DPRs having a higher propensity to phase separate and form condensed phases with higher concentrations. The critical lengths required for phase separation (25 for poly-PR and 50 for poly-GA) are comparable to the toxicity threshold limit of 30 repeats found for the expansion mutation in patient cells, suggesting that phase separation could play an important role in DPR toxicity.

Original languageEnglish
Pages (from-to)843-851
Number of pages9
JournalBiophysical Journal
Volume119
Issue number4
Early online date16-Jul-2020
Publication statusPublished - 18-Aug-2020

    Keywords

  • INTRINSICALLY DISORDERED PROTEINS, SEQUENCE DETERMINANTS, HEXANUCLEOTIDE REPEAT, ANTISENSE TRANSCRIPTS, NUCLEAR-IMPORT, GGGGCC REPEAT, RNA FOCI, EXPANSION, ALS, DOMAIN

ID: 130989523