Combating deleterious phase transitions in neurodegenerative disease

Protein aggregation is a hallmark of neurodegenerative diseases. However, the mechanism that induces pathogenic aggregation is not well understood. Recently, it has emerged that several of the pathological proteins found in an aggregated or mislocalized state in neurodegenerative diseases are also able to undergo liquid-liquid phase separation (LLPS) under physiological conditions. Although these phase transitions are likely important for various physiological functions, neurodegenerative disease-related mutations and conditions can alter the LLPS behavior of these proteins, which can elicit toxicity. Therefore, therapeutics that antagonize aberrant LLPS may be able to mitigate toxicity and aggregation that is ubiquitous in neurodegenerative disease. Here, we discuss the mechanisms by which aberrant protein phase transitions may contribute to neurodegenerative disease. We also outline potential therapeutic strategies to counter deleterious phases. State without borders: Membrane-less organelles and liquid-liquid phase transitions edited by Vladimir N Uversky.

Automated summary

Protein aggregation is a hallmark of neurodegenerative diseases, but the mechanisms behind pathogenic aggregation remain unclear. Recent studies show that certain pathological proteins linked to neurodegenerative diseases can undergo liquid-liquid phase separation under physiological conditions, potentially leading to toxicity. Therapeutic strategies targeting aberrant phase transitions may offer a way to mitigate the toxicity and aggregation seen in these diseases.