Neuronal biomolecular condensates and their implications in neurodegenerative diseases

Abstract

Biomolecular condensates are subcellular organizations where functionally related proteins and nucleic acids are assembled through liquid–liquid phase separation, allowing them to develop on a larger scale without a membrane. However, biomolecular condensates are highly vulnerable to disruptions from genetic risks and various factors inside and outside the cell and are strongly implicated in the pathogenesis of many neurodegenerative diseases. In addition to the classical view of the nucleation-polymerization process that triggers the protein aggregation from the misfolded seed, the pathologic transition of biomolecular condensates can also promote the aggregation of proteins found in the deposits of neurodegenerative diseases. Furthermore, it has been suggested that several protein or protein-RNA complexes located in the synapse and along the neuronal process are neuron-specific condensates displaying liquid-like properties. As their compositional and functional modifications play a crucial role in the context of neurodegeneration, further research is needed to fully understand the role of neuronal biomolecular condensates. In this article, we will discuss recent findings that explore the pivotal role of biomolecular condensates in the development of neuronal defects and neurodegeneration.

Understanding enzyme kinetics on coacervate as a substrate hub

“…These include stress granules and processing bodies (P-bodies) that recruit mRNA and RNA-binding proteins through liquid-liquid phase separation (LLPS). [1][2][3][4] Investigations into the fate of these organelles, as well as their responsive to stimuli such as pH, 5 redox potential, 6 light, [7][8] enzymes, [9][10] among others, could enhance the comprehension of important biological events including protein condensate formation, [11][12] substrate translocation, 13 and genomes regulation. 10 For example, condensed P-bodies are believed to physically protect the constituting mRNA from ribonuclease degradation, yet decay of specific substrate may still occur in these hubs.…”

Phase Separation Modulates the Thermodynamics and Kinetics of RNA Hybridization

“…Ribonucleoprotein (RNP) granules are biomolecular condensates composed of RNAs and proteins that are involved in key aspects of RNA metabolism such as its processing, translation, stability, and transport . Mutations in proteins and RNA molecules comprising RNP granules that alter their propensity to form condensates play a role in a variety of neurodegenerative and neurodevelopmental diseases. , Characterizing the structure and dynamics of RNA and protein molecules in these condensates is key to understanding RNP granule function and the structural transitions underlying the formation of aberrant condensates in disease. It has been shown that condensates can alter the secondary and tertiary structures and the unfolding energetics of RNA molecules, , as well as the catalytic activities of RNA enzymes .…”