The liquid phase nature of intracellular condensates has implications not only for physiological function, but also for its dysregulation in disease. Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimers, and Huntington's disease are associated with solid-like protein inclusions comprised of semi-crystalline amyloid fibers. Interestingly, many of the key IDR/LCS proteins found in RNP bodies are also implicated in these pathologies. Moreover, even in healthy cells, RNP bodies do not always appear to be pure liquids, and often exhibit partially solid-like features. In a review in 2012, we suggested that RNP bodies may represent metastable liquid phases, which can transition into more solid-like forms that could underlie the onset of various protein aggregation pathologies (Weber Cell 2012). Work from our own and other groups has recently provided strong evidence in support of this concept, showing that many liquid phase droplets are indeed metastable. For example, after sitting on a coverslip for several hours, droplets of the fungal protein Whi3 begin to nucleate fibers (Zhang Mol Cell 2015), while droplets of the nucleolar protein FIB1 become progressively more gel-like over time, consistent with time-dependent viscoelastic properties in vivo (Feric Cell 2016).

Figure - Adapted from Weber Cell 2012. Biomolecules are capable of not only condensing into a liquid form (LLPS), but can undergo phase transitions into solid like assemblies.