Membraneless organelles (MLOs), also known as biomolecular condensates, are a form of cell compartmentalization. Unlike classic membrane-bound organelles (e.g. mitochondrion, nucleus or lysosome), MLOs are not separated from their surroundings by a lipid bilayer. MLOs are mostly composed of proteins and nucleic acids, held together by weak intermolecular forces.
MLOs are present in the cytoplasm (e.g. stress granules, processing bodies) and in the nucleus (e.g. nucleolus, nuclear speckles). They have been shown to serve various functions: they can store and protect cellular material during stress conditions, they participate in gene expression and they are involved in the control of signal transduction.
It is now widely believed that MLOs form through LLPS. This was first proposed after observing that Cajal bodies and P granules show liquid-like properties, and was later confirmed by showing that liquid condensates can be reconstituted from purified protein and RNA in vitro. However, whether MLOs should be referred to as liquids, remains disputable. Even if initially they are liquid-like, over time some of them maturate into solids (gel-like or even crystalline, depending on the extent of spatial ordering within the condensate).
Many proteins participating in the formation of MLO contain so-called intrinsically disordered regions (IDRs), parts of the polypeptide chain that can adopt multiple secondary structures and form random coils in solution. IDRs can provide interactions responsible for LLPS, but over time conformational changes (sometimes promoted by mutations or post-translational modifications) may lead to the formation of higher ordered structures and solidification of MLOs. Some MLOs serve their biological role as solid particles (e.g. Balbiani body stabilised by β-sheet structure), but in many cases transformation from liquid to solid results in the formation of pathological aggregates. Examples of both liquid-liquid phase separating and aggregation-prone proteins include FUS, TDP-43 and hnRNPA1. Aggregates of these proteins are associated with neurodegenerative diseases (e.g. amyotrophic lateral sclerosis, or frontotemporal dementia).