REAL

Phase Separation of C9orf72 Dipeptide Repeats Perturbs Stress Granule Dynamics

Boeynaems, S. and Bogaert, E. and Kovács, D. and Konijnenberg, A. and Timmerman, E. and Tompa, Péter (2017) Phase Separation of C9orf72 Dipeptide Repeats Perturbs Stress Granule Dynamics. MOLECULAR CELL, 65 (6). pp. 1-18. ISSN 1097-2765

[img]
Preview
Text
1_s2.0_S1097276517301284_main_u.pdf

Download (4MB) | Preview

Abstract

Liquid-liquid phase separation (LLPS) of RNA-binding proteins plays an important role in the formation of multiple membrane-less organelles involved in RNA metabolism, including stress granules. Defects in stress granule homeostasis constitute a cornerstone of ALS/FTLD pathogenesis. Polar residues (tyrosine and glutamine) have been previously demonstrated to be critical for phase separation of ALS-linked stress granule proteins. We now identify an active role for arginine-rich domains in these phase separations. Moreover, arginine-rich dipeptide repeats (DPRs) derived from C9orf72 hexanucleotide repeat expansions similarly undergo LLPS and induce phase separation of a large set of proteins involved in RNA and stress granule metabolism. Expression of arginine-rich DPRs in cells induced spontaneous stress granule assembly that required both eIF2α phosphorylation and G3BP. Together with recent reports showing that DPRs affect nucleocytoplasmic transport, our results point to an important role for arginine-rich DPRs in the pathogenesis of C9orf72 ALS/FTLD. © 2017 The Authors

Item Type: Article
Uncontrolled Keywords: protein aggregation; prion-like domain; phase transition; low complexity domain; LLPS; Intrinsically disordered protein; hnRNP; FUS; FRONTOTEMPORAL LOBAR DEGENERATION; amyotrophic lateral sclerosis
Subjects: Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia > QH3015 Molecular biology / molekuláris biológia
SWORD Depositor: MTMT SWORD
Depositing User: MTMT SWORD
Date Deposited: 27 Feb 2018 11:43
Last Modified: 27 Feb 2018 11:43
URI: http://real.mtak.hu/id/eprint/75155

Actions (login required)

Edit Item Edit Item