Liquid droplets and hydrogels: protein phase transition in health and disease

Pathological accumulations of the RNA-binding protein FUS are observed in the nerve cells of some patients dying of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). In a recent series of ground-breaking discoveries, we have shown that FUS transiently assembles into liquid protein droplets and small jelly-like granules (ribonucleoprotein granules) inside cells. This property, which is driven by a disordered low complexity domain of FUS, allows FUS to transport, store and process RNA and protein molecules that are critical for synaptic connections between neurons. Disease-causing mutations convert this reversible process into an irreversible process. 

We wish to understand normal assembly of the liquid protein droplets and how this goes wrong in disease. To accomplish this, we will apply a series of innovative tools, together with the expertise of the applicants in neurobiology, protein folding, RNA biology and biophysics.

Many other human proteins have similar LC domains and some cause disease. FUS itself is involved both in neurodegenerative disease and in cancer. Knowledge arising from this project will therefore inform a new area of biology and will provide previously unimagined clues to new ways to diagnose and treat patients with diseases caused by FUS and similar proteins.