Liquid–liquid phase separation in neurodegenerative diseases

Liquid–liquid phase separation (LLPS) of proteins and nucleic acids leads to the formation of membrane-less organelles that play a major role in cellular organization. Recent studies provide rapidly growing evidence that LLPS may also contribute to the pathogenesis of age-related neurodegenerative diseases such as amyotrophic lateral sclerosis, frontotemporal dementia, and Alzheimer's disease. Indeed, many proteins associated with these disorders have been shown to undergo LLPS under physiologically relevant conditions, and dysregulation of their LLPS behavior can lead to cellular dysfunction and formation of toxic protein aggregates. In this chapter, we discuss the LLPS of several key neurodegenerative disease-associated proteins that highlight our growing understanding of the link between phase separation and neurodegenerative disease.