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

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.

Keywords: Huntington’s Disease; Oxidative stress; redox changes; transcriptional processes.

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. 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. 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. 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.).