Biomolecular condensates and their role in the development of neurodegenerative diseases

Abstract

Biomolecular condensates are emerging as a widespread organizational mechanism within the cell, to which an increasing number of proteins and processes are being linked, underscoring the need for systematic assessment. In this review, a framework for what constitutes a biologically relevant biocondensate was established and used to assess available phase-separation evidence for several neurodegenerative disease-associated proteins, concluding that TDP-43, tau, α-synuclein, and ataxin 2 assemble into biologically relevant biocondensates. Furthermore, the biomolecular condensates undergo a liquid-to-solid transition driven by the percolation of the underlying interaction network, and facilitate the formation of amyloid-like protein aggregates, illustrating how biomolecular condensates may contribute to the development of neurodegenerative diseases (NDDs). Moreover, NDD-associated protein sequence features, mutations, and post-translational modifications accelerate protein aggregation, thereby highlighting their potential role in disease onset and progression. Further research should focus on identifying the cellular triggers and structural rearrangements that drive the conversion from percolated biomolecular condensates to pathological protein aggregates.