In recent years, liquid-liquid phase separation (LLPS) has been rapidly developed in cell biology because of its unique function and organization. Proteins and nucleic acids (mostly RNA) in cells form membraneless organelles (MLOs) through phase transition mediated by various weak multivalent interactions and conformational entropy. These membraneless structures have distinct fluid properties, including the circular appearance, which can infiltrate, drip, fuse with each other, and have a dynamic exchange of internal components. The MLOs formed in vivo are widely involved in many important intracellular signaling processes, including cell membrane signaling, membrane binding protein assembly, chromatin remodeling, RNA metabolism, synaptic transmission, active transcription center formation, mitotic structure formation and pathological transformation of proteins. This review introduces the universality and importance of phase separation in signal regulation from the following aspects, including its discovery, molecular mechanism, the physiological activities involved in cells as well as the relationship between abnormal phase separation and neurological diseases or cancer. We also describe the experimental methods and databases related to phase separation. The discovery of LLPS of biological macromolecules provides a new perspective for us to understand many structural and cellular biological phenomena. As a new biological process, the phase separation of biomolecules may help us re-understand the regulation of many signaling pathways and
hopefully provide a new direction for the treatment of related diseases.

A series of compartments separating different biomolecules exist to ensure specificity and efficiency of biochemical reactions and regulation processes within living cells. Aside from membrane-bound organelles, membraneless organelles exist to condense proteins and nucleic acids in different granules so as to guarantee efficiency of biochemical reactions in specific spatiotemporal conditions. Mounting evidence indicates liquid-liquid phase separation (LLPS) as an important mechanism in mediating assembly of membraneless granules. This paper introduces the possible assembling mechanism of membraneless granules; then moves on to summarize the function of some membraneless granules and illustrates the role phase separation plays when they perform physiological functions. We also summarize some phase separation databases and the experimental evidences that they collected. This article expects to review the formation, biological function and data resources of membraneless compartments to inspire researchers and promote the application of high-throughput methods in this field.

Cells are compartmentalized by numerous membrane-enclosed organelles and membraneless compartments as well, to ensure a wide variety of cellular activities occurring in a spatially and temporally controlled manner. The mechanisms responsible for formation of these membraneless compartments such as nucleoli have long remained elusive. Recent studies suggest that liquid-liquid phase separation (LLPS) might serve as a critical nucleation step in formation of membraneless compartments. Besides, ever-increasing data suggests that LLPS are involved in distinct functions in cells, such as biochemical reaction centers, signaling hubs and supporting architectures. Biomolecular condensates form via transient and multivalent intermolecular forces, which mainly includes LLPS of intrinsically disordered proteins/regions (IDPs/IDRs) and specific interactions between multiple repeat domains, with and without nucleic acids. Conditions such as component concentration, pH, and post-translational modifications may alter the strength of molecular multivalent interactions, thereby regulating phase separation and phase transition processes. Aberrant phase transitions into gel-like or solid-like aggregates might play an important role in various neurodegenerative diseases, such as ALS (amyotrophic lateral sclerosis), AD (Alzheimer’s disease), HD (Huntington’s disease) and PD (Parkinson’s disease), all featuring pathologic protein aggregation. Several pathological proteins, such as TDP-43, FUS, Ataxin-2 and Tau, undergo LLPS under physiological conditions, and are likely important for various physiological functions. However,neurodegenerative disease-related mutations and conditions can alter the LLPS behavior of these proteins, thereby eliciting toxicity and form many of the hallmark pathologies. It is noteworthy that, whether these hallmark pathologies are directly causative factors of neurodegenerative disease still await further clarification.

In recent years, liquid-liquid phase separation of biological macromolecules has attracted great attention. Phase separation refers to a special state of biological macromolecules gathering in cells, and its structure is considered to be a "membrane-less organelle". Membrane-less organelles mediate multiple physiological processes and play key roles in gene expression, signal transduction, stress response and so on. Phase separation is dynamically changing and homeostatic under normal physiological state. However, abnormal phenomenon of phase separation suggests the development of diseases, such as neurodegenerative diseases, tumors, inflammation, and so on. Neurodegenerative diseases induced cognitive, motor, and language impairment, are a diverse set of disorders in which dysfunction or loss of neurons and neuronal myelin sheaths. The mechanisms of these diseases include gene mutations, abnormal protein aggregation, oxidative stress, and mitochondrial dysfunction. Overaggregation of proteins have been regarded as phase separation in neurodegenerative diseases, such as Alzheimer’s disease induced by microtubule-associated protein-Tau overaggregation, amyotrophic lateral sclerosis induced by fused in sarcoma/translocated in liposarcoma, and other related neurodegenerative diseases. Post-translational modification plays an important role in regulating the cell biological function, which, as a result, leads to aberrant phase separation through phosphorylation, methylation, acetylation and post-translational modification. This article reviews the concept of phase separation, the biochemical basis of phase separation, and particularly focusing on the role of post-translational modification mediated phase separation in neurodegenerative diseases.