An international research collaboration led by Rutgers University-New Brunswick scientists that examined microscopic blobs of protein found in human cells has discovered that some morph from an almost honey-like substance to a hard candy-like solid.
These mysterious droplets, known as biomolecular condensates, solidify when they carry a high proportion of the protein alpha-synuclein, the scientists reported in Science Advances. Clumps of alpha-synuclein are commonly found in the brain cells of people with Parkinson's disease, a neurodegenerative brain disorder.
The scientists said their discovery marks the first successful effort known to quantify condensate dynamics in live cells and highlights the importance of studying the mechanical properties of biomolecular condensates, which are linked to a wide range of biological functions and diseases.
"By measuring how these condensates change from liquid to solid in living systems, we can better understand how diseases like Parkinson's develop and progress," said Zheng Shi , an assistant professor in the Department of Chemistry and Chemical Biology in the Rutgers School of Arts and Sciences and senior author of the study.
In the past 15 years, scientists have employed advanced technologies to achieve a detailed look at biomolecular condensates, which lack a membrane boundary. They have designated them as important for understanding cell biology and origins of disease.
Rutgers scientists have zeroed in on those microscopic blobs of protein in the hopes of exploring new cell mechanisms.
"Our study has allowed us to identify factors that trigger the liquid-to-solid transition of these condensates," said Shi, who also is a member of the Cancer Pharmacology Program at the Rutgers Cancer Institute of New Jersey .
In patients with Parkinson's, the brain cells that produce dopamine – a brain chemical that is crucial for movement control – die. The disease progresses over time, with symptoms worsening as more neurons are lost.
Alpha-synuclein plays a critical role in Parkinson's disease, as the protein misfolds and clumps, forming pathological forms called Lewy bodies, which are toxic to neurons.
To make their findings, the scientists developed a set of tools that would allow them to overcome previous limitations that only allowed measurements in test tubes.
"This is exciting because our technique allows, for the first time, direct, quantitative measurement of the material properties of condensates in live cells," said Huan Wang, a doctoral student in the Department of Chemistry and Chemical Biology and the first author of the study. "It's a technological leap that opens new ways to study protein condensates."
The key was to develop tools as tiny as the biomolecular condensates themselves that could probe the globs without destroying the cell that host these condensates.
Researchers created microscopic pipettes, called micropipettes, to accurately measure small volumes of liquids.
The technique took advantage of the capillary effect, a physical phenomenon in which liquid spontaneously rises or falls in a narrow space such as a thin glass tube.
The scientists carefully inserted micropipettes into the condensates, piercing them, and drawing out the liquid or solid material within. By controlling the pressure and observing how the condensates deform and flow inside the micropipette, the scientists measured important properties such as viscosity (how thick a liquid is) and surface tension (how a liquid holds together).
The researchers said their goal is to continue measuring and better understand the properties of condensates in living cells and their implications for diseases.
"This opens new avenues for research into the early stages of neurodegenerative diseases and their treatment," Shi said.
Other scientists from Rutgers involved in the study included: Jean Baum, a Distinguished Professor, Mengying Deng, a postdoctoral associate, and Jordan Elliott, a doctoral student, all with the Department of Chemistry and Chemical Biology; Zhiping Pang, a professor, and Xiao Su, a guest researcher of the Child Health Institute of New Jersey at Rutgers Robert Wood Johnson Medical School; and Conor McClenaghan, an assistant professor at the Center for Advanced Biotechnology and Medicine.
Dragomir Milovanovic 's group of the German Center for Neurodegenerative Diseases site in Berlin also contributed to the study.
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