(Dis)Solving the problem of aberrant protein states

Neurodegenerative diseases and other protein-misfolding disorders represent a longstanding biomedical challenge, and effective therapies remain largely elusive. This failure is due, in part, to the recalcitrant and diverse nature of misfolded protein conformers. Recent work has uncovered that many aggregation-prone proteins can also undergo liquid–liquid phase separation, a process by which macromolecules self-associate to form dense condensates with liquid properties that are compositionally distinct from the bulk cellular milieu. Efforts to combat diseases caused by toxic protein states focus on exploiting or enhancing the proteostasis machinery to prevent and reverse pathological protein conformations. Here, we discuss recent advances in elucidating and engineering therapeutic agents to combat the diverse aberrant protein states that underlie protein-misfolding disorders.