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Membraneless Organelles Could Help Scientists Better Understand Incurable Diseases
Princeton University and Washington University engineers have collaborated to create a new way to study the material structure of membraneless organelles and observe how they work. Their research could have a myriad of scientific applications and help scientists better understand incurable diseases such as amyotrophic lateral sclerosis or ALS, Huntington's disease and cancers.
Membraneless Organelles and Ribonucleic Acid
These miniscule structures are like droplet compartments, and they're present in all living cells. They use chemistry to regulate the inner workings of cells, including cell division, movement and self-destruction. The organelle droplets are the key to how cells process gene expression and stress response.
What makes them different from other organelles is that they don't have a membrane to keep them from merging with the other molecules, nucleic acids and proteins in cells. Instead, they remain as self-contained structures.
Washington University School of Engineering & Applied Science's Edwin H. Murty Professor of Engineering Rohit Pappu compares them to water droplets. However, he says that they're comprised of proteins that assemble with ribonucleic acid. RNA is a molecule formed from DNA that's responsible for synthesizing proteins and transferring genetic code.
How the Organelle Droplets Form and Dissolve
Scientists at The Scripps Research Institute have studied the formation and dissolution of organelle droplets and found that these processes occur as needed. This could be the key to cellular survival because it allows cells to adjust to cellular stress quickly. Research Associate Priya Banerjee notes that the negative charge of RNA molecules determines these processes.
Overall, RNA has a negative charge. When it encounters positively-charged proteins, they're attracted to each other. This creates a molecular cluster and forms the organelle droplets. When the presence of RNA increases, it causes an imbalance between the negative and positive charges that quickly dissolves the droplets.
Peering Into Organelle Droplets for the First Time
Observing the inner workings of membraneless organelles has been difficult in the past because they're so small. However, Princeton University School of Engineering and Applied Science's Associate Professor of Chemical and Biological Engineering Clifford Brangwynne pioneered a technique with his team to probe the droplets.
Called ultrafast scanning fluorescence correlation spectroscopy, the technique uses sound waves to control the ability of a microscope to obtain protein concentration measurements from inside the organelles. Using usFCS on cells from a roundworm, the researchers could measure the protein concentrations formed by the LAF-1 protein, which produces p-granules that polarize a cell before it divides. They were surprised that the organelle droplets weren't densely packed like they imagined. Instead, they're permeable, low-density structures.
After reviewing the findings at Washington University, Pappu says that his lab team could basically swim inside the droplets to find out how much room was inside. Rather than finding a crowded swimming pool, so to speak, they found plenty of water and room. This made them realize that not all organelle droplets are the same.
While studying the LAF-1 protein organelles, they also found that certain protein sequences are very floppy molecules like spaghetti that can't fold into defined structures. Other protein organelles, however, are more like ketchup or toothpaste and can fold into defined structures.Implications for Understanding How Diseases Develop
This research can directly help scientists understand the biological functions of organelle droplets and how material changes cause diseases such as cancers and neurodegeneration. One day, Pappu says, scientists will be able to mimic the organelles, which can help them diagnose and understand a host of diseases. These advancements could be transformative in the health care industry.