N-Acetylcysteine improves mitochondrial function and ameliorates behavioral deficits in the R6/1 mouse model of Huntington's disease

Abstract

Huntington's disease (HD) is a neurodegenerative disorder, involving psychiatric, cognitive and motor symptoms, caused by a CAG-repeat expansion encoding an extended polyglutamine tract in the huntingtin protein. Oxidative stress and excitotoxicity have previously been implicated in the pathogenesis of HD. We hypothesized that N-acetylcysteine (NAC) may reduce both excitotoxicity and oxidative stress through its actions on glutamate reuptake and antioxidant capacity. The R6/1 transgenic mouse model of HD was used to investigate the effects of NAC on HD pathology. It was found that chronic NAC administration delayed the onset and progression of motor deficits in R6/1 mice, while having an antidepressant-like effect on both R6/1 and wild-type mice. A deficit in the astrocytic glutamate transporter protein, GLT-1, was found in R6/1 mice. However, this deficit was not ameliorated by NAC, implying that the therapeutic effect of NAC is not due to rescue of the GLT-1 deficit and associated glutamate-induced excitotoxicity. Assessment of mitochondrial function in the striatum and cortex revealed that R6/1 mice show reduced mitochondrial respiratory capacity specific to the striatum. This deficit was rescued by chronic treatment with NAC. There was a selective increase in markers of oxidative damage in mitochondria, which was rescued by NAC. In conclusion, NAC is able to delay the onset of motor deficits in the R6/1 model of Huntington's disease and it may do so by ameliorating mitochondrial dysfunction. Thus, NAC shows promise as a potential therapeutic agent in HD. Furthermore, our data suggest that NAC may also have broader antidepressant efficacy.

Complete Disruption of the Kainate Receptor Gene Family Results in Corticostriatal Dysfunction in Mice

“…Consequently, 5ko mice had a significantly higher propel:brake ratio than 5het controls (Figure 2G). Similar changes have been observed in mouse models of Huntington’s disease, and demonstrate that 5ko mice have altered rhythmicity in their gate (Wright et al, 2015). …”

Brain urea increase is an early Huntington’s disease pathogenic event observed in a prodromal transgenic sheep model and HD cases

“…Interestingly, CSE is depleted in HD patient brain tissue and mouse models of HD, and this is thought to be neurotoxic due to oxidative stress caused by the loss of cysteine (55). Indeed, N-acetylcysteine has beneficial effects on motor abnormalities and weight loss in mouse models of HD (55,56). In contrast, we have previously reported elevated levels of cysteine in the OVT73 sheep cerebellum (20), perhaps reflecting a compensatory response of the cysteine biosynthesis pathway in this prodromal disease model.…”

Transcriptional control of amino acid homeostasis is disrupted in Huntington’s disease

“…Depletion of branched chain amino acids has been implicated in muscle shrinkage observed in HD (5). Similarly, a pathogenic role for cysteine deficiency in HD is supported by the beneficial effects of N-acetylcysteine (8,27) and couples with evidence for cysteine disturbances in other conditions of oxidative stress including aging, neurodegeneration, AIDS, and insulin resistance syndrome (28)(29)(30)(31)(32). Disturbances of cysteine disposition in multiple diseases may reflect a form of "cysteine stress" with widespread impact.…”