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Phase separation and neurodegenerative diseases: a disturbance in the force

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Zbinden, Aurélie, Pérez-Berlanga, Manuela, De Rossi, Pierre, Polymenidou, Magdalini·2020·Developmental Cell
DOI 10.1016/j.devcel.2020.09.014
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Abstract

Protein aggregation is the main hallmark of neurodegenerative diseases. Many proteins found in pathological inclusions are known to undergo liquid-liquid phase separation, a reversible process of molecular self-assembly. Emerging evidence supports the hypothesis that aberrant phase separation behavior may serve as a trigger of protein aggregation in neurodegeneration, and efforts to understand and control the underlying mechanisms are underway. Here, we review similarities and differences among four main proteins, α-synuclein, FUS, tau, and TDP-43, which are found aggregated in different diseases and were independently shown to phase separate. We discuss future directions in the field that will help shed light on the molecular mechanisms of aggregation and neurodegeneration.

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  • Most current LLPS studies have focused on aggregation-prone proteins, which tend to form excessive condensates under pathological conditions and subsequently undergo a liquid-to-solid transition, thereby exacerbating disease progression.

    “However, most current LLPS studies have focused on these aggregation‐prone proteins, which tend to form excessive condensates under pathological conditions and subsequently undergo a liquid‐to‐solid transition, thereby exacerbating disease progression. 24”

    From Aberrant phase separation from a rare <i>ABI3</i> mutation drives microglial dysfunction and Alzheimer's risk (2026) · cites this paper as [24]

    The review discusses aggregation-prone proteins and says that loss of condensate dynamics may trigger immobile aggregates (indexed Abstract passages; page unavailable). But it presents the link between LLPS and aggregation as a hypothesis, says a direct link is still missing, and notes that the role of aggregates in disease is debated. It does not establish that most LLPS studies focus on these proteins or that their liquid-to-solid transition generally exacerbates disease progression. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Authors
Zbinden, A., Pérez-Berlanga, M., De Rossi, P., & Polymenidou, M.
Affiliations
University of Zurich (CH)
Corresponding author
Polymenidou, Magdalini
ORCID
Venue
Developmental Cell
Publisher
Elsevier BV
Published
2020-10
Volume
55
Issue
1
Pages
45-68
ISSN
1534-5807 (ISSN-L)
DOI
10.1016/j.devcel.2020.09.014
OpenAlex
W3092508309
Cited by
500
References
21
Citations by year
2026: 79 · 2025: 112 · 2024: 112 · 2023: 79 · 2022: 72 · 2021: 41 · 2020: 4
FWCI
5.76
Type
journal article
Language
en
Open access
Licence
Locations
  • Developmental Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
  • Zurich Open Repository and Archive (University of Zurich)
Funders
  • University of California, San Diego
  • Case Western Reserve University
  • Cambridge Institute for Medical Research, University of Cambridge
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (CRSII5_170976 11)
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
liquid-liquid phase separation, neurodegenerative diseases, protein aggregation, alpha-synuclein, FUS, tau protein, TDP-43, molecular self-assembly
MeSH terms
Protein Domains, DNA-Binding Proteins, Humans, RNA-Binding Proteins, Neurodegenerative Diseases, Mechanical Phenomena, Protein Aggregates

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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