An international group of researchers has identified new processes that form protein “clumps” that are characteristic of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). How these proteins, which can bind RNA in normal cells, stick together has remained elusive until recently, when scientists demonstrated that they demix from the watery substance inside cells, much like oil separates from water. This latest research, featured on the cover of Molecular Cell, sheds light onto the molecular interactions behind the process in patients with defects in the C9orf72 gene.

Clumps of RNA-binding proteins occur naturally in normal neurons under times of stress in the form of stress granules (SGs), which precipitate from the water inside cells. However, in normal cells, the process of stress granule formation is tightly controlled, reversible and does not lead to disease. Scientists previously believed that hydrophobic interactions – or the protein’s inability to mix with water – caused the formation of stress granules. However, the researchers showed that in patients with defects in the C9orf72 gene, a different process can also cause this demixing, which precedes the formation of these toxic protein aggregates.

Stress granules normally behave as liquid protein droplets within a cell, while protein aggregates do not. The C9orf72 mutation causes neurons to produce small, abnormal and highly charged toxic proteins, or peptides. Yet, precisely how these peptides are toxic was not well-understood. The research team was able to observe in vitro that these peptides cause RNA-binding proteins to spontaneously stick together and change the dynamics of stress granules in cells, making them more like solids than liquids.

The scientists suggest that future research could focus on the development of a sort of ‘molecular antifreeze’ to prevent solidification and, thus, protein aggregation.

Paper: “Phase Separation of C9orf72 Dipeptide Repeats Perturbs Stress Granule Dynamics”
Reprinted from materials provided by VIB – Flanders Interuniversity Institute for Biotechnology.