Structural disorder and phase separation of proteins involved in ALS

Liquid-liquid phase separation (LLPS) of RNA-binding proteins plays a role in the formation of multiple membrane-less organelles involved in RNA metabolism, including stress granules [1,2]. Defects in stress granule homeostasis constitute a cornerstone of Amyotrophic lateral sclerosis (ALS)/ Frontotemporal lobar degeneration (FTLD) pathogenesis. Polar residues (tyrosine, 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 [3]. 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 at an important role for arginine-rich DPRs in the pathogenesis of C9orf72 ALS/FTLD.

[1] Tompa, P. (2013) Hydrogel formation by multivalent IDPs: a reincarnation of the microtrabecular lattice? Int. Diso. Proteins. 1, e24068

[2] Brangwynne, C. P., Tompa, P., Pappu, R. V. (2015) Polymer Physics of Intracellular Phase Transitions. Nature Physics. 11: 899–904

[3] Boeynaems, S. et al.  (2017) Phase Separation of C9orf72 Dipeptide Repeats Perturbs Stress Granule Dynamics. Mol. Cell 65: 1044–1055