Scientists have discovered that essential proteins aggregate to become defective proteins.
A lot of severe diseases involve the build-up or aggregation of misshaped proteins. Recently, a team of scientists from the University of Cambridge has discovered a new property of essential proteins which might be directly involved with protein aggregation when it becomes defective.
Most neurodegenerative diseases, such as Parkinson's or Alzheimer's disease, have one common trait: they involve the build-up of misfolded' proteins, which then cause damage to the brain.
This is also seen in other forms of diseases, such as motor neuron disease (or amyotrophic lateral sclerosis, ALS), and frontotemporal dementia. In such diseases, there is the build-up of misfolded FUS protein as well as other RNA-binding proteins. However, the mechanism of aggregation of this type of protein has several differences with conventional protein aggregates seen in Alzheimer's or Parkinson's. Because of this, until now, it is unclear how FUS proteins aggregate and the significance of this aggregation is still unknown.
FUS, as mentioned earlier, is an RNA-binding protein, and is involved in RNA transcription regulation as well as the translation of RNA into proteins. In line with these functions, they have domains to bind RNA, and also domains where the protein still appears to be unfolded or unstructured.
According to the journal published in Neuron by scientists from the University of Cambridge, FUS proteins are able to transition between a completely soluble monomer' form, and a condensed jelly-like form known as a hydrogel. While these transitions are happening, the protein assemblies capture and release RNA and other proteins. This allows for efficient transcription and translation without the use of a limiting membrane.
Using C. elegans as an ALS and frontotemporal dementia model, the study revealed that the transition from monomer to hydrogel could sometimes become irreversible. In the case of FUS and other RNA binding proteins, the healthy' proteins rarely spontaneously over-condense. However, if FUS becomes mutated, the condensation process becomes excessive and forms thick gels that are unable to return to the monomer state. Because of the formation of these thick gels, some important proteins and other structures (such as ribosomes) become trapped and are also unable to serve their function. It also disrupts the synthesis of new proteins in nerve axons.
The research was able to show that the formation of these irreversible jelly-like structures can be prevented by targeting with small molecules, thereby rescuing the worm from impaired motility and extending its lifespan.
So basically, the research shows that some proteins are able to morph from a soluble state to viscous hydrogels that allows cells to efficiently perform cellular processes, and then disassemble the machinery back to its soluble state when not needed. This seems to be more effective as compared to doing the same thing inside intracellular membrane-bound vesicles. Unfortunately though, this process can become excessive because of mutations, leading to disease.
From the team, Professor St George Hyslop says that they have shown that some proteins are able to transition between states, but this property is also a double-edged sword, in that when a mutation is present, their normal function is easily disrupted, causing disease.
The same principles are likely to be at play in other more common forms of these diseases due to the mutation in other related binding proteins. Understanding what is in these assemblies should provide further targets for disease treatments.
Prof Hyslop also says that this is also a good example of how bringing together people from the biological and physical sciences has been able to reveal the underlying causes of a disease, and also shows the importance of considering the mechanisms of disease not only as plainly biological, but also physical.
If you want to know more about proteins and their functions, feel free to read our other articles on this site.
Written by: Yevgeny Aster Dulla, MSc.