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Tau liquid‐liquid phase separation in neurodegenerative diseases

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Boyko, Solomiia, Surewicz, Witold K.·2022·Trends in Cell Biology
DOI 10.1016/j.tcb.2022.01.011PMC PMC9189016
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Abstract

Aggregation of the microtubule-associated protein tau plays a major role in Alzheimer's disease and several other neurodegenerative disorders. An exciting recent development is the finding that, akin to some other proteins associated with neurodegenerative disease, tau has a high propensity to condensate via the mechanism of liquid-liquid phase separation (LLPS). Here, we discuss the evidence for tau LLPS in vitro, the molecular mechanisms of this reaction, and the role of post-translational modifications and pathogenic mutations in tau phase separation. We also discuss recent studies on tau LLPS in cells and the insights these studies provide regarding the link between LLPS and neurodegeneration in tauopathies.

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  • In AD, tau's mutations or abnormal PTMs induce aberrant and excess LLPS, driving fibril formation and neurotoxicity.

    “In AD, tau's mutations or abnormal post‐translational modifications (PTMs) induce aberrant and excess LLPS, driving fibril formation and neurotoxicity. 25”

    From Aberrant phase separation from a rare <i>ABI3</i> mutation drives microglial dysfunction and Alzheimer's risk (2026) · cites this paper as [25]

    In “The regulatory role of LLPS in tau aggregation” (page unavailable), the review reports that pathogenic mutations accelerate fibril formation within tau droplets. But “The effect of disease-associated mutation on tau LLPS” says the tested mutations do not significantly increase tau’s intrinsic LLPS propensity. The PTM section describes effects that vary by modification, while the cellular-context section suggests a possible toxicity mechanism; neither establishes the claimed mutation/PTM-to-excess-LLPS-to-neurotoxicity pathway in AD. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Classical phase-separating proteins such as FUS, TDP-43, tau, and α-synuclein exhibit abnormal accumulation and aggregation that are closely linked to neuronal dysfunction.

    “Classical phase‐separating proteins such as FUS, 46 TDP‐43, 47 tau, 25 , 29 and α‐synuclein 48 exhibit abnormal accumulation and aggregation that are closely linked to neuronal dysfunction.”

    From Aberrant phase separation from a rare <i>ABI3</i> mutation drives microglial dysfunction and Alzheimer's risk (2026) · cites this paper as [25]

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Authors
Boyko, S., & Surewicz, W. K.
Affiliations
Case Western Reserve University (US)
Corresponding author
Surewicz, Witold K.
ORCID
Venue
Trends in Cell Biology
Publisher
Elsevier BV
Published
2022-07
Volume
32
Issue
7
Pages
611-623
ISSN
0962-8924 (ISSN-L)
DOI
10.1016/j.tcb.2022.01.011
PMC
PMC9189016
OpenAlex
W4213208979
Cited by
215
References
8
Citations by year
2026: 63 · 2025: 61 · 2024: 53 · 2023: 28 · 2022: 10
FWCI
5.13
Type
journal article
Language
en
Open access
Licence
Locations
  • Trends in Cell Biology (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institutes of Health (RF1 AG061797)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
Keywords
tau protein, liquid-liquid phase separation, tauopathy, Alzheimer's disease, protein condensation, post-translational modification, tau mutations, neurodegeneration, microtubule-associated proteins
MeSH terms
Alzheimer Disease, Humans, Mutation, Protein Processing, Post-Translational, tau Proteins, Neurodegenerative Diseases

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