AGGREGRATION of the protein FUS is a major component of the process leading to two incurable neurodegenerative diseases, according to researchers from Ludwig-Maximilians-Universität (LMU) München, Munich, Germany. The team demonstrated the mechanisms causing the pathological aggregation of FUS, findings that provide the basis for greater understanding of the pathology of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
Protein Aggregation
The FUS (FUsed in Sarcoma) protein acts as both a DNA-binding transcription factor and as a RNA-binding regulator of transcript splicing after being transported into the nucleus in healthy nerve cells. However, in ALS and FTD patients in whom the function of the neurons is affected, the transportation of FUS into the nucleus is compromised; this leads to the protein accumulating in the cytoplasm of these neurons and coagulating into stress granules. The team believed that these granules may spark the promotion of protein aggregation, leading to irreversible clumping of FUS.
The study showed that a liquid-liquid phase separation analogous to the gradual coalescence of oil droplets dispersed in an oil-water emulsion results in FUS aggregation. Liquid droplets form, in which FUS can congeal into jelly-like clumps and then solid aggregates.
Promotion of Phase Separation
Promotion of these phase changes of FUS occurs in different ways in both ALS and FTD. In ALS, the proteins’ ability to bind to the nuclear import receptor Transportin, which FUS must interact with to get into the nucleus, is weakened by mutations in FUS. The stabilising function Transportin has for proteins like FUS is also compromised by these mutations. In FTD, while the FUS protein is normal, a small chemical modification on FUS that regulates its transport into the nucleus is defective. The study shows that failure to modify the protein promotes phase separation and aggregation of FUS in the cytoplasm in addition to affecting its intracellular transport.
Neurodegenerative Disease Development
As well as displaying the significance of aggregation of FUS to the process leading to ALS and FTS, the research provides the basis for further studies looking at the mechanisms behind neurodegenerative disorders.
“Furthermore, accumulating evidence strongly supports the idea that other proteins implicated in the pathology of neurodegenerative disorders can form aggregates via phase separation,” commented Dr Dorothee Dormann, LMU. “We will now take a closer look at these proteins in order to understand how this process is normally suppressed, and how it might be modulated chemically.”
James Coker, Reporter
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