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Cited by 71Alzheimer's disease research and treatmentsHistone Deacetylase Inhibitors ResearchRedox biology and oxidative stress

Increased acetylation of Peroxiredoxin1 by HDAC6 inhibition leads to recovery of Aβ-induced impaired axonal transport

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Choi, Heesun, Kim, Haeng Jun, Kim, Jisoo, Kim, Soohyun, Yang, Jinhee, Lee, Wonik, Park, Yeonju, Hyeon, Seung Jae +4 more·2017·Molecular Neurodegeneration
DOI 10.1186/s13024-017-0164-1PMC PMC5330132
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Abstract

Reduction or inhibition of histone deacetylase 6 (HDAC6) has been shown to rescue memory in mouse models of Alzheimer’s disease (AD) and is recently being considered a possible therapeutic strategy. However, the restoring mechanism of HDAC6 inhibition has not been fully understood. Here, we found that an anti-oxidant protein Peroxdiredoxin1 (Prx1), a substrate of HDAC6, malfunctions in Aβ treated cells, the brains of 5xFAD AD model mice and AD patients. Malfunctioning Prx1, caused by reduced Prx1 acetylation levels, was recovered by HDAC6 inhibition. Increasing acetylation levels of Prx1 by HDAC6 inhibition recovered elevated reactive oxygen species (ROS) levels, elevated Ca 2+ levels and impaired mitochondrial axonal transport, sequentially, even in the presence of Aβ. Prx1 mutant studies on the K197 site for an acetylation mimic or silencing mutation support the results showing that HDAC6 inhibitor restores Aβ-induced disruption of ROS, Ca 2+ and axonal transport. Taken together, increasing acetylation of Prx1 by HDAC6 inhibition has several beneficial effects in AD pathology. Here, we present the novel mechanism by which elevated acetylation of Prx1 rescues mitochondrial axonal transport impaired by Aβ. Therefore, our results suggest that modulation of Prx1 acetylation by HDAC6 inhibition has great therapeutic potential for AD and has further therapeutic possibilities for other neurodegenerative diseases as well.

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  • Brains of patients with AD exhibit prominent hallmarks of oxidative damage and decreased PRDX1 acetylation and thiol-reductive activity.

    “Brains of patients with AD exhibit prominent hallmarks of oxidative damage and decreased PRDX1 acetylation and thiol-reductive activity (47, 48) that could collectively impair GDE2 trafficking and function.”

    From GDE2-RECK controls ADAM10 α-secretase–mediated cleavage of amyloid precursor protein (2021) · cites this paper as [48]

    The Results section reports decreased PRDX1 acetylation in the hippocampus and entorhinal cortex of patients with AD, and cites elevated oxidative-damage markers in AD brains (page not available). The paper links PRDX1 acetylation to antioxidant function, but does not report a measurement of decreased thiol-reductive activity in patient brains; its activity evidence comes from cell experiments and a cited prior study. (LLM, conf=0.86)

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Cited by

Sorted by citations

Authors
Choi, H., Kim, H. J., Kim, J., Kim, S., Yang, J., Lee, W., Park, Y., Hyeon, S. J., Lee, D.-S., Ryu, H., Chung, J., & Mook-Jung, I.
Affiliations
  • Seoul National University (KR)
  • Korean Association Of Science and Technology Studies (KR)
  • Boston University (US)
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2017-02-28
Volume
12
Issue
1
Pages
23-23
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/s13024-017-0164-1
PMC
PMC5330132
OpenAlex
W2592057173
Cited by
71
References
6
Citations by year
2026: 4 · 2025: 7 · 2024: 13 · 2023: 6 · 2022: 5 · 2021: 5 · 2020: 15 · 2019: 4 · 2018: 10 · 2017: 2
FWCI
6.68
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Seoul National University Open Repository (Seoul National University) (submittedVersion)
Funders
  • National Research Foundation of Korea (2014M3C7A1046047, 2015M3C7A1028790)
  • Medical research center (2012R1A5A2A44671346)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords
HDAC6 inhibition, protein acetylation, amyloid-beta, Alzheimer's disease, axonal transport, mitochondrial transport, reactive oxygen species, calcium dysregulation, 5xFAD mice, neurodegeneration therapy
MeSH terms
Acetylation, Alzheimer Disease, Animals, Axonal Transport, Brain, Disease Models, Animal, Histone Deacetylases, Humans, Immunohistochemistry, Mice, Transgenic, Neurons, Transfection, Blotting, Western, Amyloid beta-Peptides, Immunoprecipitation, Mice, Peroxiredoxins, Histone Deacetylase Inhibitors

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