Intrinsically Disorder Proteins and Liquid-Liquid Phase Transitions in Neurodegenerative Diseases

Neurodegenerative diseases have a negative impact on health and economics, effecting more than 20 million people in the United States and costing around $800 billion in 2018. Additionally, most neurodegenerative diseases such as Alzheimer’s Disease (AD), Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), and several others are fatal and have no cure or effective treatment. Many of these diseases have a common theme of protein aggregates being present in disease tissue. These aggregates are thought to be toxic to the cell and prevention of pathological aggregation and elimination of these cellular aggregates may serve as a potential therapeutic approach to treat disease. Furthermore, identifying a common mechanism shared in all diseases that seeds the toxic aggregation of proteins would enable therapeutic approaches that prevent protein aggregation to be more broadly applicable. Here we demonstrate the ability of intrinsically disordered proteins found in neurodegenerative diseases to undergo liquid-liquid phase separation and show that this can seed their aggregation and lead to detrimental effects on the cell. We also show that this behavior can be modulated by exploited ratios of expressed pathological proteins as well as increasing the expression of chaperone proteins. This work offers some key insight to a potential mechanism shared across several neurodegenerative disease related proteins that could be targeted in order to alleviate disease progression