Role of aberrant phase separation in pathological protein aggregation

Abstract

Neurodegenerative diseases are associated with the pathological deposition of many different intrinsically disordered proteins or proteins with intrinsically disordered regions. Recent evidence suggests that these proteins can undergo liquid-liquid phase separation and also form membrane-less organelles in cells. Additionally, the biomolecular condensates formed by these proteins may undergo liquid-to-solid phase transition thereby maturating to amyloid fibrils, oligomeric species, or amorphous aggregates and contributing to the pathology of several neurodegenerative diseases. Here we discuss the role of phase separation of the neuronal proteins tau, α-synuclein, fused in sarcoma (FUS), and the transactive response DNA-binding protein of 43 kDa (TDP-43) that are associated with neurodegeneration in the context of pathological protein aggregation.