Defective ribonucleoprotein (RNP) granules are thought to be a major factor in the development of amyotrophic lateral sclerosis (ALS) and other forms of neurodegenerative disease, while they are also associated with a number of other conditions. We spoke to Professor Simon Alberti about his work in investigating how these granules form and how they cause disease. Molecular aging of a prion-like RNA-binding protein from a liquid to a solid, aggregated state.
How do RNP granules cause disease? The aggregation of mis-folded proteins in the body is known to be a major factor in the development of certain neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). While younger people are able to essentially clear these mis-folded proteins, this ability declines as we age, which can eventually lead to serious health problems. “The protein quality control (PQC) machinery controls the status of these proteins and keeps them in check. We think that starts to fail as people age,” explains Simon Alberti, Professor of Cellular Biochemistry at TU Dresden. As the Principal Investigator of the PhaseAge project, Professor Alberti is investigating the factors behind this gradual loss of function, looking in particular at the role of ribonucleoprotein (RNP) granules. “These RNP granules are considered to be membraneless organelles as they contain a lot of different factors, such as proteins and RNAs, and they have no membranes around them.” he says.
Many different conditions are associated with defective RNP granules, including not just neurodegenerative diseases, but also a number of other disorders, underlining the wider importance of Professor Alberti’s research. These RNP granules become defective when they undergo a transition from a liquid-like state into an aberrant, more solid state. “The important point with this transition is that the dynamics change. The proteins are essentially trapped inside, and there’s little exchange with the outside,” outlines Professor Alberti. The wider aim of his research is to understand the molecular mechanism behind both the formation of these RNP granules and their transition into an aberrant state. “We want to understand the molecular principles of how these granules form, and how they turn into something that can cause disease. And, most importantly, can we then find factors that can prevent these transitions?” says Professor Alberti.
RNP granules The first step towards this wider goal is to understand how these RNP granules are initially formed inside a cell, with researchers looking at the role of proteins in this process. It is thought that initially RNA-binding proteins and other factors assemble into these membraneless organelles, or RNP granules, within a cell. “At first the properties are maintained, but as we age, we lose the ability to control the material properties of these structures,” says Professor Alberti. By analysing single cells, Professor Alberti and his colleagues hope to gain deeper insights into how these RNP granules are formed, how they age, and how this may affect disease development. “We are looking at healthy cells, while we also mimic ageing in cells. Essentially, we stress the cells, as we know that ageing very often increases stress,” he outlines. “We also purify RNA-binding proteins, then using these proteins we try to put together these structures that normally we only see in cells.”
Liquid-like properties of RNP granules.
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