• "We used new optical techniques to observe the transition of protein aggregates from liquid to solid, which can be as fast as less than a second or as slow as a few minutes, thus better tracking the process of protein aggregation.”
• "Our findings are expected to fundamentally improve the understanding of neurogenic diseases, which means a promising new area of research to better understand the development of Alzheimer's and myotrophic lateral sclerosis in the brain.”
With the increase of human life expectancy, the prevalence of neurodegenerative diseases increases year by year.Pathological protein aggregation is considered one of the important characteristics of neurodegenerative diseases. In Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD), protein aggregation is often used as a basis for diagnosis and classification.However, knowledge of protein aggregation is still limited, which hinders the cause and treatment of neurodegenerative diseases.
Recently, Dr. Shen Yi, a researcher at the School of Chemistry and Biomolecular Engineering at the University of Sydney, Australia, and scientists from Cambridge and Harvard University have developed complex optical technologies to monitor protein aggregates.The study was published in the Proceedings of the National Academy of Sciences (PNAS) on August 24, 2023.This is the world's first nano-optical observation of the process, which is expected to better understand the occurrence and development of neurodegenerative diseases in the brain.
"The aggregation of pathogenic proteins in neurological diseases has been very difficult to observe because it is on a nanometer scale (one-millionth of a meter)," Shen's team explained in an interview with Pompai Technology.Existing techniques include electron microscopy, atomic force microscopy, and fluorescence microscopy, but most of these can only see the results, and it is difficult to see the transition process.We used new optical techniques to observe the transition of protein aggregates from liquid to solid, which can be as fast as less than a second or as slow as a few minutes.”
The study supports a new theory that the protein aggregation that causes neurological disorders may be preceded by liquid-liquid phase separation (LLPS).Liquid-liquid phase separation refers to the separation of a mixture of chemicals (such as proteins, nucleic acids, etc.) in the liquid phase (the state of matter being liquid, and only liquid, no solid or gas in this system), forming two or more independent liquid phases.These liquid phases have different physical and chemical properties and can be transformed into each other by means of material transport mechanisms such as diffusion and transportation.
A more popular example would be to put water and oil together, and even if they were stirred from the start, the two liquids would spontaneously separate and form an interface.Liquid-liquid phase separation refers to the spontaneous separation of different liquids.
Liquid-liquid phase separation is a concept in polymer physics, but in recent years, more and more studies have shown that the process of liquid-liquid phase separation is closely related to life process.Protein molecules in cells are all present in the cytoplasm in the form of droplets, so biological cells can be treated as a complex mixture of fluids.
Many diseases affecting the brain and nervous system are associated with the formation of protein aggregates or solid condensates in cells that change from liquid to solid, which trigger the formation of amyloid fibres and further plaques in neurons.
Shen Yi's team used a new optical technology to monitor FUS proteins associated with amyotrophic lateral sclerosis. FUS proteins are separated in liquid-liquid phase under certain conditions to form protein droplets.Gel formation begins at the edge, spreads to the center, and finally forms a core-shell structure.
The FUS protein was separated by liquid-liquid phase according to ion intensity, and then the density of condensate changed from homogeneous to locally heterogeneous.Photo Credit: The University of Sydney Research Paper
Amyotrophic lateral sclerosis, also known as amyotrophic lateral sclerosis, is a rare disease that affects 6-9 people worldwide and gradually shrinks to paralysis, but remains conscious.The famous astrophysicist Prof. Hawking, former vice president of Jingdong Cai Lei, and anti-epidemic hero Zhang Dingyu are all frozen patients.
"The transition from liquid to solid increases the risk of aggregation dysfunction, i.e. unhealthy solid protein aggregates in human cells," said lead author Shen Yi, who led the study.Therefore, it is important to monitor condensate dynamics because they directly affect pathological status."Our research has taken a big step forward in understanding the development of brain disease from a fundamental perspective.”
In addition, through nanoscale optical observations, the team was able to determine that the transition from liquid to solid proteins began at the interface of protein condensates.And the internal structure of these aggregates is heterogeneous, which was previously considered homogeneous."Our findings are expected to fundamentally improve understanding of neurogenic diseases, which means a promising new area of research to better understand the development of Alzheimer's disease and myotrophic lateral sclerosis in the brain, potentially affecting millions of people worldwide." Dr. Danielle Vigolo, a senior lecturer at the University of Sydney's School of Biomedical Engineering and a member of the University of Sydney's Nano Institute, said.
Shen Yi's team told Pengpai that the limitation of its research is that it is difficult to observe specific proteins in cells. Next, they want to combine fluorescent markers to solve this problem.
Previous studies have found that Tau proteins play a role in Alzheimer's disease, characterized by abnormal and pathogenic changes in Tau protein conformation, oligomerization of proteins, and increased phosphorylation of Tau proteins.In June 2020, an article published by Nature Communications revealed liquid-liquid phase separation of Tau proteins, which may contribute to the formation of non-filamentally pathogenic Tau protein conformation.Shen Yi's team told Pompai Technology that the optical technology could also be used to further study the aggregation of Tau proteins.