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Aberrant Phase Transitions: Side Effects and Novel Therapeutic Strategies in Human Disease.

ABSTRACT: Phase separation is a physiological process occurring spontaneously when single-phase molecular complexes separate in two phases, a concentrated phase and a more diluted one. Eukaryotic cells employ phase transition strategies to promote the formation of intracellular territories not delimited by membranes with increased local RNA concentration, such as nucleolus, paraspeckles, P granules, Cajal bodies, P-bodies, and stress granules. These organelles contain both proteins and coding and non-coding RNAs and play important roles in different steps of the regulation of gene expression and in cellular signaling. Recently, it has been shown that most human RNA-binding proteins (RBPs) contain at least one low-complexity domain, called prion-like domain (PrLD), because proteins harboring them display aggregation properties like prion proteins. PrLDs support RBP function and contribute to liquid-liquid phase transitions that drive ribonucleoprotein granule assembly, but also render RBPs prone to misfolding by promoting the formation of pathological aggregates that lead to toxicity in specific cell types. Protein-protein and protein-RNA interactions within the separated phase can enhance the transition of RBPs into solid aberrant aggregates, thus causing diseases. In this review, we highlight the role of phase transition in human disease such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and in cancer. Moreover, we discuss novel therapeutic strategies focused to control phase transitions by preventing the conversion into aberrant aggregates. In this regard, the stimulation of chaperone machinery to disassemble membrane-less organelles, the induction of pathways that could inhibit aberrant phase separation, and the development of antisense oligonucleotides (ASOs) to knockdown RNAs could be evaluated as novel therapeutic strategies for the treatment of those human diseases characterized by aberrant phase transition aggregates.

SUBMITTER: Verdile V

PROVIDER: S-EPMC6440380 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Aberrant Phase Transitions: Side Effects and Novel Therapeutic Strategies in Human Disease.

Verdile Veronica V De Paola Elisa E Paronetto Maria Paola MP

Frontiers in genetics 20190322

Phase separation is a physiological process occurring spontaneously when single-phase molecular complexes separate in two phases, a concentrated phase and a more diluted one. Eukaryotic cells employ phase transition strategies to promote the formation of intracellular territories not delimited by membranes with increased local RNA concentration, such as nucleolus, paraspeckles, P granules, Cajal bodies, P-bodies, and stress granules. These organelles contain both proteins and coding and non-codi ...[more]

PMID: 30967892

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Project description:Protein condensations, such as crystallization, liquid-liquid phase separation, aggregation, and gelation, have been observed in concentrated antibody solutions under various solution conditions. While most IgG antibodies are quite soluble, a few outliers can undergo condensation under physiological conditions. Condensation of IgGs can cause serious consequences in some human diseases and in biopharmaceutical formulations. The phase transitions underlying protein condensations in concentrated IgG solutions is also of fundamental interest for the understanding of the phase behavior of non-spherical protein molecules. Due to the high solubility of generic IgGs, the phase behavior of IgG solutions has not yet been well studied. In this work, we present an experimental approach to study IgG solutions in which the phase transitions are hidden below the freezing point of the solution. Using this method, we have investigated liquid-liquid phase separation of six human myeloma IgGs and two recombinant pharmaceutical human IgGs. We have also studied the relation between crystallization and liquid-liquid phase separation of two human cryoglobulin IgGs. Our experimental results reveal several important features of the generic phase behavior of IgG solutions: (1) the shape of the coexistence curve is similar for all IgGs but quite different from that of quasi-spherical proteins; (2) all IgGs have critical points located at roughly the same protein concentration at ~100 mg/ml while their critical temperatures vary significantly; and (3) the liquid-liquid phase separation in IgG solutions is metastable with respect to crystallization. These features of phase behavior of IgG solutions reflect the fact that all IgGs have nearly identical molecular geometry but quite diverse net inter-protein interaction energies. This work provides a foundation for further experimental and theoretical studies of the phase behavior of generic IgGs as well as outliers with large propensity to condense. The investigation of the phase diagram of IgG solutions is of great importance for the understanding of immunoglobulin deposition diseases as well as for the understanding of the colloidal stability of IgG pharmaceutical formulations.

Dataset Information

Aberrant Phase Transitions: Side Effects and Novel Therapeutic Strategies in Human Disease.

Publications

Aberrant Phase Transitions: Side Effects and Novel Therapeutic Strategies in Human Disease.

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