Acetylation Disfavors Tau Phase Separation
Open accessAbstract
Neuropathological aggregates of the intrinsically disordered microtubule-associated protein Tau are hallmarks of Alzheimer’s disease, with decades of research devoted to studying the protein’s aggregation properties both in vitro and in vivo. Recent demonstrations that Tau is capable of undergoing liquid-liquid phase separation (LLPS) reveal the possibility that protein-enriched phase separated compartments could serve as initiation sites for Tau aggregation, as shown for other amyloidogenic proteins, such as the Fused in Sarcoma protein (FUS) and TAR DNA-binding protein-43 (TDP-43). Although truncation, mutation, and hyperphosphorylation have been shown to enhance Tau LLPS and aggregation, the effect of hyperacetylation on Tau aggregation remains unclear. Here, we investigate how the acetylation of Tau affects its potential to undergo phase separation and aggregation. Our data show that the hyperacetylation of Tau by p300 histone acetyltransferase (HAT) disfavors LLPS, inhibits heparin-induced aggregation, and impedes access to LLPS-initiated microtubule assembly. We propose that Tau acetylation prevents the toxic effects of LLPS-dependent aggregation but, nevertheless, contributes to Tau loss-of-function pathology by inhibiting Tau LLPS-mediated microtubule assembly.
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LLPS may initiate tau aggregation, and this process is enhanced by tau phosphorylation, and impaired by acetylation.
“LLPS may initiate tau aggregation, and this process is enhanced by tau phosphorylation, and impaired by acetylation [225–227].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [227]
Phosphorylation and acetylation have been demonstrated to exert a regulatory effect on liquid-liquid phase separation.
“Phosphorylation and acetylation have been demonstrated to exert a regulatory effect on LLPS [58,59,60,61].”
From Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review (2024) · cites this paper as [60]
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- Authors
- Ferreon, J. C., Jain, A., Choi, K.-J., Tsoi, P. S., MacKenzie, K. R., Jung, S. Y., & Ferreon, A. C.
- Affiliations
- Baylor College of Medicine (US)
- Corresponding author
- Ferreon, Josephine C.
- Ferreon, Allan Chris
- ORCID
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2018-05-04
- Volume
- 19
- Issue
- 5
- Pages
- 1360
- ISSN
- 1422-0067 (ISSN-L)
- PMC
- PMC5983838
- OpenAlex
- W2799629087
- Cited by
- 183
- References
- 45
- Citations by year
- 2026: 17 · 2025: 19 · 2024: 23 · 2023: 18 · 2022: 28 · 2021: 31 · 2020: 20 · 2019: 25 · 2018: 1 · 2014: 1
- FWCI
- 13.20
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- International Journal of Molecular Sciences (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- tau protein, acetylation, liquid-liquid phase separation, protein aggregation, Alzheimer's disease, P300, histone acetyltransferase, microtubule assembly, intrinsically disordered proteins, amyloidogenic proteins
- MeSH terms
- Acetylation, Alzheimer Disease, DNA-Binding Proteins, Heparin, Humans, Microtubules, Phosphorylation, tau Proteins, p300-CBP Transcription Factors, Liquid-Liquid Extraction, Intrinsically Disordered Proteins, Protein Aggregation, Pathological
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