Protein condensation diseases: therapeutic opportunities

Abstract

Condensed states of proteins, including liquid-like membraneless organelles and solid-like aggregates, contribute in fundamental ways to the organisation and function of the cell. Perturbations of these states can lead to a variety of diseases through mechanisms that we are now beginning to understand. We define protein condensation diseases as conditions caused by the disruption of the normal behaviour of the condensed states of proteins. We analyze the problem of the identification of targets for pharmacological interventions for these diseases and explore opportunities for the regulation of the formation and organisation of aberrant condensed states of proteins.

Sequence-based Prediction of the Cellular Toxicity Associated with Amyloid Aggregation within Protein Condensates

“…The possibility for proteins of populating different states creates a challenge for the protein homeostasis system, since dysregulated transitions into nonfunctional assemblies can generate pathological processes. 12,16 In particular, aging condensates often appear to cause cytotoxicity and to be associated with neurological disorders. 25,36,37 In this study, we have investigated the amino acid code of the cytotoxicity of aging protein condensates.…”

“…Upon dysregulation of the balance between the native state and the droplet state, however, the latter can evolve into the amyloid state (Figure ). During this process of amyloid formation, known as the condensation pathway, cytotoxic intermediates can be generated. − Cytotoxicity can be caused by a wide variety of molecular mechanisms, including protein mislocalization, a lack of availability of functional partners, or a presence of nonphysiological partners, and by changes in the protein structure, leading to oligomerization. In addition, a delayed reconversion to the native state of proteins trapped in a gel-like form can be due to recruitment of other cellular components …”

Ultrafast molecular dynamics observed within a dense protein condensate

“…This highly dynamic regime of interactions may contribute to a faster local exploration of binding partners in condensates and efficient biochemical reactions. Similarly, the kinetics of molecular self-assembly processes that require large rearrangements of the chain, including the formation of amyloid-like structures within condensates (6, 43), may not be strongly hindered by the dense yet liquid-like environment.…”

Protein interactions: anything new?

“…Recent discoveries highlight that, in addition to specific protein complexes, higher-order assemblies, ranging from ordered amyloids to dense liquid droplets, contribute to a wide range of biological activities [1]. In particular, there is an emerging interest in physiological and pathological roles of biomolecular condensates, generated by liquid-liquid phase separation [2][3][4][5]. Are the principles governing the formation of higher-order assemblies different from those driving specific protein assembly?…”