Biomolecular Phase Separation in Neurodegenerative Diseases

Biomolecular phase separation is a fundamental cellular process in which proteins and nucleic acids condense into dynamic, membrane-less assemblies known as biomolecular condensates. These structures, governed by multivalent interactions among intrinsically disordered regions and modular binding motifs, organise biochemical reactions in time and space. In healthy neurons, condensates such as stress granules and RNA-protein granules orchestrate RNA metabolism, local translation and stress responses. However, genetic mutations or post-translational modifications can perturb the material properties of these assemblies, driving a transition from reversible liquid-like droplets to pathological gels or insoluble aggregates. Such aberrant phase transitions are increasingly implicated in the aetiology of amyotrophic lateral sclerosis, frontotemporal dementia and related neurodegenerative disorders. The misregulated condensation of RNA-binding proteins can impair synaptic function, disrupt nucleocytoplasmic transport and trigger neuronal death. Understanding the biophysical principles and regulatory mechanisms underlying condensate formation offers new insights into disease progression and highlights novel avenues for therapeutic intervention, including small molecules or chaperones that restore healthy condensate dynamics.

Research from Nature Portfolio

Recent studies have revealed that loss of splicing repression by the RNA-binding protein TDP-43 occurs in the earliest stages of amyotrophic lateral sclerosis–frontotemporal dementia, even before clinical symptoms arise. A newly developed monoclonal antibody specific to a cryptic epitope identifies aberrant TDP-43 activity in cerebrospinal fluid and blood, providing a fluid biomarker that detects presymptomatic protein misregulation. This advance not only clarifies the temporal onset of pathological phase transitions in TDP-43 condensates but also establishes a platform for early diagnosis and monitoring of therapeutic efficacy in clinical trials.

Biomolecular Phase Separation in Neurodegenerative Diseases publication trend

The graph below shows the total number of articles in biomolecular phase separation in neurodegenerative diseases across all publications each year (not limited to Nature Index journals).

Technical terms

Biomolecular condensates: Dynamic, membrane-less assemblies formed by phase separation of proteins and nucleic acids that concentrate specific biochemical activities.

Phase separation: The process by which a homogeneous mixture of biomolecules demixes into distinct dense and dilute phases, akin to oil separating from water.

Intrinsically disordered regions (IDRs): Protein segments lacking fixed three-dimensional structure that mediate flexible, multivalent interactions driving condensate formation.

Liquid-liquid phase separation (LLPS): A reversible condensation process yielding liquid-like droplets that exchange components with the surrounding cellular milieu.

Low-complexity domains: Protein regions enriched in a limited set of amino acids that facilitate weak, multivalent interactions and modulate condensate material properties.

References

1. Emerging regulatory mechanisms and functions of biomolecular condensates: implications for therapeutic targets. Signal Transduction and Targeted Therapy (2025).
2. A fluid biomarker reveals loss of TDP-43 splicing repression in presymptomatic ALS–FTD. Nature Medicine (2024).
3. ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function. Neuron (2015).
4. FUS Phase Separation Is Modulated by a Molecular Chaperone and Methylation of Arginine Cation-π Interactions. Cell (2018).