A Role for Oxidized DNA Precursors in Huntington's Disease–Like Striatal Neurodegeneration

Abstract

Several human neurodegenerative disorders are characterized by the accumulation of 8-oxo-7,8-dihydroguanine (8-oxodG) in the DNA of affected neurons. This can occur either through direct oxidation of DNA guanine or via incorporation of the oxidized nucleotide during replication. Hydrolases that degrade oxidized purine nucleoside triphosphates normally minimize this incorporation. hMTH1 is the major human hydrolase. It degrades both 8-oxodGTP and 8-oxoGTP to the corresponding monophosphates. To investigate whether the incorporation of oxidized nucleic acid precursors contributes to neurodegeneration, we constructed a transgenic mouse in which the human hMTH1 8-oxodGTPase is expressed. hMTH1 expression protected embryonic fibroblasts and mouse tissues against the effects of oxidants. Wild-type mice exposed to 3-nitropropionic acid develop neuropathological and behavioural symptoms that resemble those of Huntington's disease. hMTH1 transgene expression conferred a dramatic protection against these Huntington's disease–like symptoms, including weight loss, dystonia and gait abnormalities, striatal degeneration, and death. In a complementary approach, an in vitro genetic model for Huntington's disease was also used. hMTH1 expression protected progenitor striatal cells containing an expanded CAG repeat of the huntingtin gene from toxicity associated with expression of the mutant huntingtin. The findings implicate oxidized nucleic acid precursors in the neuropathological features of Huntington's disease and identify the utilization of oxidized nucleoside triphosphates by striatal cells as a significant contributor to the pathogenesis of this disorder.

8-Oxoguanine causes neurodegeneration during MUTYH-mediated DNA base excision repair

“…It has been established that administration of 3-NP to rodents and nonhuman primates replicates most of the clinical and pathophysiological hallmarks of HD, including spontaneous choreiform and dystonic movements, frontal-type cognitive deficits, and progressive heterogeneous striatal degeneration, at least partially by apoptosis (26). We have shown that increased expression of human MTH1 in mouse striatum efficiently suppresses such striatal degeneration, accompanied by effective suppression of the 8-oxoG accumulation in the striatum induced by 3-NP (27). However, it is not clear to what extent 8-oxoG accumulated in DNA is responsible for the neurodegeneration, because MTH1 can hydrolyze oxidized forms of ATP, GTP, and dATP as well as dGTP (28).…”

“…Overexpression of human MTH1 in mouse striatum efficiently abrogates 3-NP-induced striatal degeneration accompanied by effective suppression of 8-oxoG accumulation in the striatum (27). Mth1/Ogg1-DKO mice exhibited the highest susceptibility MUTYH deficiency ameliorates 3-NP-induced motor impairments and striatal degeneration in Ogg1-KO mice.…”

“…MTH1 also efficiently suppresses the accumulation of 8-oxoG in mtDNA in the hippocampus caused by kainate-induced excitotoxicity, especially in microglia (43). Moreover, it has been shown that human MTH1 transgenic mice are resistant to 3-NP-induced striatal degeneration (27), suggesting that increased accumulation of 8-oxoG in brain causes neurodegeneration.…”

Moieties in antidiabetic drugs as a target of insulin receptors in association with common neurological disorders

“…Disruption of this equilibrium would give rise to cell damage, elicit disorders in the physiological state and foster pathological process such as neurodegenerative disorders, and DNA 8-oxo-7,8-dihydroguanine accumulation due to the integration of oxidized nucleotide resulting from replication or due to the oxidation of DNA guanine (14). Similarly, the mitochondrial respiratory chain becomes the principal site of superoxide radical production.…”

Manipulating Glia to Protect Retinal Ganglion Cells in Glaucoma

“…Oxidative stress can result from exposure to stimuli that range from environmental toxins, infection and energy dysregulation to ischemia; it has been implicated in several neurodegenerative diseases, including glaucoma (Gmitterova et al, 2009). Resolution of oxidative stress can halt neurodegeneration (De Luca et al, 2008). As will be discussed at length in the section on optic nerve head, increased IOP can affect blood flow to the retina.…”