Liquid-liquid phase separation of amyloid-like proteins in neurodegenerative diseases

Neurodegenerative diseases are diseases caused by the progressive death or loss of function of cells and neurons in the brain and peripheral nervous system, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) and others. Due to the incomplete understanding of the pathological mechanisms of neurodegenerative diseases, currently available treatment methods can only alleviate some related symptoms, and there remains a lack of effective treatment methods. Most neurodegenerative diseases share a common cellular and molecular mechanism, which is the formation of amyloid-like protein aggregates and inclusion bodies. The widespread presence of protein aggregates in neurodegenerative diseases suggests their special role in disease occurrence and progression. For a long time, nucleation and aggregation was considered as the only way for protein aggregate formation. However, recent studies suggest that these proteins may undergo another aggregation process, which is liquid-liquid phase separation mediated aggregation. Phase separation is the process by which biomolecules form dynamic condensates through weak multivalent interactions. In these condensates, the biomolecule concentration is highly enriched and still maintains dynamic exchange with the external environment. Phase separation is mediated by weak multivalent interactions such as electrostatic, pi-related, hydrogen bonding, and hydrophobic interactions. For specific molecules, their phase separation behavior may be mainly mediated by one or some interactions. However, interactions in living systems are more complex. There has been a lot of work looking at the types of interactions that make major contributions in various systems. These findings may help us further understand how phase separation behaviors can be altered by small perturbatians on the sequences and why naturally occurring mutations produce significant physiological and biophysical effects. Proteins that undergo phase separation in living organisms usually contain intrinsically disordered regions (IDRs), or intrinsically disordered proteins (IDPs). Amyloid-like proteins usually have such disordered characteristics. Such IDRs/ IDPs do not have stable folding structures and exist in a dynamic form in solution. Due to the lack of a clear three-dimensional structure, IDRs/IDPs have higher dynamism and flexibility, thus providing more opportunities for intermolecular contact and interaction. In recent years, researchers have shown that many neurodegenerative disease-related amyloid-like proteins can undergo phase separation, suggesting a potential association between the phase behavior of amyloid-like proteins and pathology. Here, we summarized recent studies on the phase separation and aggregation of several neurodegenerative disease-related amyloid-like proteins, including A beta, Tau, alpha-synuclein, TDP-43 and SOD1. They are typical pathologic proteins associated with neurodegenerative diseases and have been shown to have a high correlation with related diseases over the past few decades. Their common feature is the amyloid aggregates found in the patients. Recent research has shown that they also have the property of phase separation, which may correlate to the formation of pathological aggregates. Therefore, we summarized the latest research on the phase behavior of these amyloid proteins, which may bring potential opportunities for regulating the associated pathological processes and treating diseases. We hope this article can help deepen the understanding of pathological mechanisms of proteins in neurodegenerative diseases and inspire new ideas for disease treatment.