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.

Keywords: RNA transport granule; biomolecular condensates; liquid–liquid phase separation; neurodegenerative disease; phase transition; protein aggregation; synapse.

Figure 1

Neuronal condensates at the physiologic and pathologic contexts. (A) RNP granules, which are composed of mutant proteins encoded by amyotrophic lateral sclerosis (ALS)–frontotemporal dementia (FTD) causing genes, undergo a phase transition to solid states, resulting in the formation of protein aggregates. (B) Both posttranslational modification such as phosphorylation of synapsin by CaMKII dispersion and changes in interacting molecules (e.g., α-synuclein) lead to the dispersion of synaptic vesicle (SV) cluster. (C) Coexisting phase of scaffolding proteins serve as a hub to accommodate other presynaptic active zones (AZ) proteins. (D) The interaction between SynGAP trimer and PSD-95 plays a crucial role in assembling postsynaptic density. (E) RNA transport granules, either alone or with lysosomes, travel bi-directionally along the microtubule tract.