Biomolecular droplets accelerate proteins in age-related diseases
The increase of life expectancy has increased the risk of diseases involving pathological amyloid formation (such as Parkinson’s or Alzheimer’s disease). Despite the prevalence of these diseases, it is still poorly understood what triggers the aggregation of amyloidogenic proteins in the cell. A major challenge is to determine whether small droplets, which are also found in human cells as biomolecular condensates, have a positive or negative influence on the formation of protein aggregates. Evan Spruijt, researcher from the Institute for Molecules and Materials (IMM) of Radboud University demonstrated that biomolecular condensates can both accelerate and slow down amyloid formation. This could shed new light on the mechanism of amyloid formation and the onset of amyloid-related diseases. The results have been published in Science Advances.
The research team studied the protein alpha-synuclein (Parkinson’s disease) to determine how fast the aggregates are formed. “We have studied three different kinds of droplets (coacervates) and created a new variant of the protein which lights up when the protein enters the aggregate to ensure we could measure both where and when aggregates form”, Spruijt explains. They found that condensates can speed up amyloid formation when proteins localize to their interface. However, condensates can also slow down aggregation by sequestering and stabilizing amyloidogenic proteins. “Especially where the protein alpha-synuclein sticks to the edge of the droplets, we see faster aggregation. If the protein is completely incorporated into the droplets, this can slow down aggregation and therefore possibly delay the formation of harmful protein aggregates”, Spruijt says.
With the results of the study, there is better understanding how (and where) the aggregates that eventually lead to Parkinson’s or Alzheimer’s disease are most likely first formed. In future studies the research team will investigate if these conditions also occur in human cells and how the protein localization can be altered. “We would like to design small molecules that modify these droplets in such a way that they can slow down aggregation and therefore defer the start of these kinds of diseases even more.”
Evan Spruijt is head of the Soft Interfaces group, which is part of the Physical Organic Chemistry department. The research group is part of the IMM. The group aims to create artificial organelles that can be used as functional compartments in synthetic cells or as model systems to elucidate the role of coacervates in cells and in the origin of life. The group studies if natural selection and molecular evolution between different coacervate species could result from the natural tendency of coacervates to take up other molecules.
Biomolecular condensates can both accelerate and suppress aggregation of α synuclein
Wojciech P. Lipiński, Brent S. Visser, Irina Robu, Mohammad A. A. Fakhree, Saskia Lindhoud,
Mireille M. A. E. Claessens, Evan Spruijt
Science Advances (2022)
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