CoChat
Sign Up
Cited by 236Genetic Neurodegenerative DiseasesRedox biology and oxidative stressParkinson's Disease Mechanisms and Treatments

The DOI matches its Crossref record; 183 of the 183 references it cites were found in a registry or an index.

Oxidative Stress and Huntington’s Disease: The Good, The Bad, and The Ugly

Open access
Kumar, Amit, Ratan, Rajiv R.·2016·Journal of Huntington s Disease
DOI 10.3233/jhd-160205PMC PMC5310831
Open this paper in CoChat — free accountOpen PDF

Abstract

Redox homeostasis is crucial for proper cellular functions, including receptor tyrosine kinase signaling, protein folding, and xenobiotic detoxification. Under basal conditions, there is a balance between oxidants and antioxidants. This balance facilitates the ability of oxidants, such as reactive oxygen species, to play critical regulatory functions through a direct modification of a small number of amino acids (e.g. cysteine) on signaling proteins. These signaling functions leverage tight spatial, amplitude, and temporal control of oxidant concentrations. However, when oxidants overwhelm the antioxidant capacity, they lead to a harmful condition of oxidative stress. Oxidative stress has long been held to be one of the key players in disease progression for Huntington's disease (HD). In this review, we will critically review this evidence, drawing some intermediate conclusions, and ultimately provide a framework for thinking about the role of oxidative stress in the pathophysiology of HD.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3233/jhd-160205

Cites

183 of 183 references verified0 citation errors · 0 not checkable

Statistics

Figures

Fig. 1 A brief overview of involvement of reactive oxygen species in multiple physiological and pathological functions as signaling molecules. Recent findings have placed ROS as very critical signaling factors which are involved in regulating not only pathological functions but also in a host of functions necessary for normal cellular function. Therefore, a very careful attention is needed before considering antioxidants as therapeutic options for Huntington’s disease.
Fig. 1 A brief overview of involvement of reactive oxygen species in multiple physiological and pathological functions as signaling molecules. Recent findings have placed ROS as very critical signaling factors which are involved in regulating not only pathological functions but also in a host of functions necessary for normal cellular function. Therefore, a very careful attention is needed before considering antioxidants as therapeutic options for Huntington’s disease.CC BY-NC · PubMed Central
Fig. 2 A coupled chain of oxidation-repair cycle leads to expansion and instability of huntingtin polyglutamine repeats. DNA oxidation induces an adaptive response in the form of recruitment of DNA repair enzymes. These enzymes are recruited in response to either hairpin loop structure or other secondary structures formed either because of oxidized bases and/or base mismatches leading to strand slippage and instability. Moreover, a complex cyclic interplay between oxidized bases and DNA repair enzymes leads to further expansion of trinucleotide repeats and its instability.
Fig. 2 A coupled chain of oxidation-repair cycle leads to expansion and instability of huntingtin polyglutamine repeats. DNA oxidation induces an adaptive response in the form of recruitment of DNA repair enzymes. These enzymes are recruited in response to either hairpin loop structure or other secondary structures formed either because of oxidized bases and/or base mismatches leading to strand slippage and instability. Moreover, a complex cyclic interplay between oxidized bases and DNA repair enzymes leads to further expansion of trinucleotide repeats and its instability.CC BY-NC · PubMed Central
Fig. 3 A schematic representation of redox regulation of different kinds of transcriptional processes. A. An example of the redox regulation of the TF binding to the promoters of its target genes through an upstream regulator, Ref-1. A number of TFs have one or more reactive cysteines in their DNA binding domain, which are redox regulated by Ref-1 (APE-1) protein, which, in turn, is also redox regulated through its reactive cysteine. B. An example of the redox regulation of the TF binding to the promoters of its target genes under oxidative stress. The binding of Sp-1/Sp-3 to the promoters of its target genes is also redox regulated. Under basal condition, the binding of Sp-1/Sp-3 is very weak while oxidative stress induces their strong binding with the promoters of their target genes, which has been shown to be neuroprotective by our group. C. An example of indirect redox regulation of TFs by the change in redox states of co-factors such as NAD and NADH. The binding of CTBP-1, a co-repressor regulating the expression of BDNF with transcription factor NRSF depends upon NAD/NADH ratio. D. An example of the regulation of transcriptional processes through redox associated post-translation modifications. Redox regulation of HDAC2 through S-nitrosylation leads to its release, which, in turn, increases acetylation and enhances CREB dependent transcription.
Fig. 3 A schematic representation of redox regulation of different kinds of transcriptional processes. A. An example of the redox regulation of the TF binding to the promoters of its target genes through an upstream regulator, Ref-1. A number of TFs have one or more reactive cysteines in their DNA binding domain, which are redox regulated by Ref-1 (APE-1) protein, which, in turn, is also redox regulated through its reactive cysteine. B. An example of the redox regulation of the TF binding to the promoters of its target genes under oxidative stress. The binding of Sp-1/Sp-3 to the promoters of its target genes is also redox regulated. Under basal condition, the binding of Sp-1/Sp-3 is very weak while oxidative stress induces their strong binding with the promoters of their target genes, which has been shown to be neuroprotective by our group. C. An example of indirect redox regulation of TFs by the change in redox states of co-factors such as NAD and NADH. The binding of CTBP-1, a co-repressor regulating the expression of BDNF with transcription factor NRSF depends upon NAD/NADH ratio. D. An example of the regulation of transcriptional processes through redox associated post-translation modifications. Redox regulation of HDAC2 through S-nitrosylation leads to its release, which, in turn, increases acetylation and enhances CREB dependent transcription.CC BY-NC · PubMed Central
Fig. 4 Increases in Sp1 and Sp3 DNA binding induced by the glutamate analog HCA are inhibited by antioxidants. Sp1 and Sp3 DNA binding in cortical neurons are activated by hydrogen peroxide. Induction of Sp1 and Sp3 DNA binding by HCA-induced glutathione depletion (4 hr) is decreased by the antioxidant iron chelator DFO (100 %m; A) and the lipid peroxidation inhibitor BHA (10 %m; B). C, Addition of exogenous peroxide, generated by the enzyme DAAO and its substrate d-ala (20 mm) for 4 hr increases Sp1 and Sp3 DNA binding in a concentration-dependent manner in cortical neurons. The induction is observed despite no morphological or biochemical evidence of cell death in cortical neurons. D, Addition of catalase abrogates Sp1 and Sp3 DNA binding induced by d-ala (20 mm) and DAAO (5 mU). Examples are representative of three to five independent experiments. (With permission from J. Neurosci.).
Fig. 4 Increases in Sp1 and Sp3 DNA binding induced by the glutamate analog HCA are inhibited by antioxidants. Sp1 and Sp3 DNA binding in cortical neurons are activated by hydrogen peroxide. Induction of Sp1 and Sp3 DNA binding by HCA-induced glutathione depletion (4 hr) is decreased by the antioxidant iron chelator DFO (100 %m; A) and the lipid peroxidation inhibitor BHA (10 %m; B). C, Addition of exogenous peroxide, generated by the enzyme DAAO and its substrate d-ala (20 mm) for 4 hr increases Sp1 and Sp3 DNA binding in a concentration-dependent manner in cortical neurons. The induction is observed despite no morphological or biochemical evidence of cell death in cortical neurons. D, Addition of catalase abrogates Sp1 and Sp3 DNA binding induced by d-ala (20 mm) and DAAO (5 mU). Examples are representative of three to five independent experiments. (With permission from J. Neurosci.).CC BY-NC · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 183 references

Research works printed but not linked: 4

  1. Huntington Study Group T-HDI, 2008, Arch Neurol, 65, 1582
  2. 10.1093/hmg/ddw051 · DOI
  3. Entezam A, 2010, Hum Mutat, 31, 611
  4. Brocardo PS, Rejuvenation Res, 2016

Cited by

Sorted by citations

Related

See all

Metadata

Authors
Kumar, A., & Ratan, R. R.
Affiliations
Cornell University (US)
Corresponding author
Ratan, Rajiv R.
ORCID
Venue
Journal of Huntington s Disease
Publisher
SAGE Publications
Published
2016-09-20
Volume
5
Issue
3
Pages
217-237
ISSN
  • 1879-6397 (ISSN-L)
  • 1879-6400
DOI
10.3233/jhd-160205
PMC
PMC5310831
OpenAlex
W2522941116
Cited by
236
References
183
Citations by year
2026: 19 · 2025: 32 · 2024: 31 · 2023: 26 · 2022: 34 · 2021: 31 · 2020: 21 · 2019: 20 · 2018: 18 · 2017: 4
FWCI
1.53
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Huntington s Disease (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by-nc)
Funders
  • Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
  • National Institutes of Health (P01 AG14930-15A1)
  • National Institute on Aging (P01AG014930, AG14930)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
Keywords
oxidative stress, Huntington's disease, redox homeostasis, reactive oxygen species, antioxidants, cysteine oxidation, protein oxidation, receptor tyrosine kinase signaling, protein folding, xenobiotic detoxification, disease pathophysiology
MeSH terms
Humans, Huntington Disease, Oxidative Stress

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 ›

Are you an author, or do you see a problem with this page? Request a review