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.
Highlights
Eukaryotic cells are characterized by morphologically distinct compartments displaying multiple roles in biological processes
Nucleus is characterized by the presence of nucleoli that are involved in the ribosome biogenesis; paraspeckles, whose formation is promoted by the long non-coding RNA (lncRNA) NEAT1, that interacts with several RNA-binding proteins (RBPs), including FUS, in the core, and TDP-43 in the shell; Cajal bodies that are involved in the small nuclear ribonucleoprotein (snRNP) biogenesis; and super-enhancers that are clusters of master transcription factors and transcriptional co-activators involved in gene expression
This review explores individual membrane-less organelles (MLOs), with emphasis on how they contribute to biological functions and how their dysregulation promotes the development of human disease
Summary
Transitions: Side Effects and Novel Therapeutic Strategies in Human Disease. Front. 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. We discuss novel therapeutic strategies focused to control phase transitions by preventing the conversion into aberrant aggregates.
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