Unraveling the mysteries of brain diseases–when proteins get stuck in solids

Viewing proteins at the nanoscale provides insights for the treatment of neurodegenerative diseases.

Many diseases affecting the brain and nervous system are associated with the formation of protein aggregates, or solid condensates, in cells from their liquid condensates, yet little is known about this process.

This transition from liquid to solid can lead to the formation of so-called amyloid fibrils. These can form plaques in nerve cells, causing neurodegenerative diseases such as: Alzheimer’s disease.

Biomedical engineers at the University of Sydney, in collaboration with scientists from the University of Cambridge and Harvard University, have developed sophisticated optical techniques to monitor from close range the process by which these protein aggregates are formed.

By testing a protein associated with the disease amyotrophic lateral sclerosis (ALS), which affects astrophysicist Professor Stephen Hawking, Sydney engineers closely monitored the transition from its liquid to solid phase.

3D confocal scanning microscopy of FUS protein condensate incubated for 24 h showing the characteristic core-cortex structure revealed by this research. credit: f Sydney University

“This is a huge step forward towards understanding how neurological diseases develop from a fundamental perspective,” said Dr. Yi Xin, lead author of the research published in the journal Neurology. Proceedings of the National Academy of Sciences (PNAS) in the United States.

“We can now directly observe the transition of these important proteins from liquid to solid at nanoscale “It’s a millionth of a metre,” said Dr Daniel Figullo, senior lecturer in the School of Biomedical Engineering and a member of the University of Sydney’s Nano Institute.

Proteins regularly form condensates during liquid-to-liquid phase separation in a wide range of critical and healthful biological functions, such as the formation of human embryos. This process aids biochemical reactions where protein concentrations are critical and also promotes healthy protein-protein interactions.

Vigolo and Shane’s research team. Credit: University of Sydney

“However, this process also increases the risk of dysfunctional aggregation, whereby unhealthy aggregates of rigid proteins form in human cells,” said Dr Shen, an ARC DECRA Fellow in the School of Chemical and Biomolecular Engineering and a member of Sydney Nano. .

“This can lead to abnormal structures associated with neurodegenerative diseases because the proteins no longer show a rapid reversibility back to the liquid form. It is therefore necessary to monitor the dynamics of the condensers, as they directly affect disease states,” she said.

The world’s first nanoscale optical observation of this process allowed the team to determine that the transition from a liquid protein to a solid protein begins at the interface of the protein adsorbates. This window into the transition also revealed that the internal structures of these protein aggregates are heterogeneous, as they were previously thought to be homogeneous.

Dr Vigolo said: “Our findings promise to greatly improve our understanding of neurological diseases from a fundamental perspective.

“This means a promising new area of ​​research to better understand how Alzheimer’s disease and ALS progress in the brain, affecting millions of people worldwide.”

Reference: “FUS transition from liquid to solid is enhanced by surface condensate” by Yi Shen, Anqi Chen, Wenyun Wang, Yinan Shen, Francesco Simone Ruggeri, Stefano Aime, Zizhao Wang, Seema Qamar, Jorge R. Espinosa, Adiran Garrizar, Available Here. Peter St. George Heslop, Rosanna Colibardo Guevara, David A. Weitz, Danielle Figullo and Thomas PJ Knowles, August 7, 2023, Available Here. Proceedings of the National Academy of Sciences.
doi: 10.1073/pnas.2301366120

The study was funded by the Francis and Augustus Newman Foundation, the Wellcome Trust, the European Research Council, the American Alzheimer’s Association, ALS Canada-Brain Canada, the Canadian Institutes of Health Research, and the National Institute on Aging.