Protein Aggregation and Disaggregation in Cells and Development

Abstract

Protein aggregation is a feature of numerous neurodegenerative diseases. However, regulated, often reversible, formation of protein aggregates, also known as condensates, helps control a wide range of cellular activities including stress response, gene expression, memory, cell development and differentiation. This review presents examples of aggregates found in biological systems, how they are used, and cellular strategies that control aggregation and disaggregation. We include features of the aggregating proteins themselves, environmental factors, co-aggregates, post-translational modifications and well-known aggregation-directed activities that influence their formation, material state, stability and dissolution. We highlight the emerging roles of biomolecular condensates in early animal development, and disaggregation processing proteins that have recently been shown to play key roles in gametogenesis and embryogenesis.

Keywords: ABCF gene family; RuvBL gene family; amyloid; biomolecular condensate; chaperone.

Figure 1.. Material states and their biological correlates.

(A) Equilibria and reversibility between different condensate material states highlighting the range and diversity of their structural organization and the strategies used by the cell to transition from one state to the next. (B) Functional roles of reversible condensates. Left, yeast (Cdc19) has a stabilizing amyloid core. Right, granules such as the Balbiani body or the nucleolus consist of multiple material states, which may contribute to their stability and aggregation/disaggregation dynamics. (C) One-way changes to an amyloid or amyloid-like conformation are needed for some functions. Left, cell-cell interactions by adhesins in Candida albicans, Middle, aggregation of Orb2 in Drosophila melanogaster for long-term memory formation and right, structural amyloids such as the protective chorion layer of oocytes. Purple wavy lines represent RNA. Filled blue circles represent ordered domains and light blue lines represent intrinsically disordered domains of proteins. Black lines represent oligomers. Figure created with Biorender.com. Oocyte in panel C adapted from [72].