The mutation of an RNA-binding protein, FUS, triggers it to irreversibly form gel-like clumps and impair normal neuron function, suggesting a possible mechanism and target for neurodegenerative diseases.
There is no truly effective treatment for neurodegenerative diseases like Alzheimer’s disease, frontotemporal dementia, and amyotrophic lateral sclerosis. This grim reality has spurred neuroscientists to search for new causative cellular mechanisms and therapeutic targets in hope for a cure. A University of Toronto-based group led by Dr. Peter St. Geroge-Hyslop, has uncovered evidence that a protein, FUS, already known to form clumps in the diseased brain, may be a potential target for ALS and dementia therapies.
FUS is a RNA-binding protein that regulates localized protein synthesis, or the creation of proteins, by delivering protein components to various locations in the neuron. It was reported that FUS has the ability to morph from a gel to a liquid state. While in gel form, FUS picks up cell components needed to make proteins, and reverts back to a liquid to release the components so protein synthesis can take place at the required location in the neuron. This process helps keep the neuron healthy and functioning normally.
Using an invertebrate model, the research group showed experimentally that a mutation in a specific region of FUS inhibited its ability to change states, causing it to irreversibly remain as a gel, unable to release protein components, and form clumps. One can speculate that FUS dysfunction could have profound effects in motor neurons, which have processes up to a meter long that extend from the spinal cord to muscles or glands. The inability of FUS to control local protein synthesis far from the neuronal body negatively impacts the health of motor neurons and may contribute to their degeneration in disease like ALS. It is unknown as to whether the clumping of FUS also has pathological consequences in dementias, like frontotemporal dementia, that are characterized by the clumping of another protein called alpha synuclein, so further research into this possibility is required.
Murakami et al., ALS/FTD mutation-induced phase transition of FUS liquid droplets and reversible hydrogels into irreversible hydrogels impairs RNP granule function. Neuron, 88(1): 1-13, 2015.
Written by Fiona Wong, PhD