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

Wright, D. J., Renoir, T., Smith, Z. M., Frazier, A. E., Francis, P. S., Thorburn, D. R., McGee, S. L., Hannan, A. J. and Gray, L. J. 2015, N-Acetylcysteine improves mitochondrial function and ameliorates behavioral deficits in the R6/1 mouse model of Huntington's disease, Translational psychiatry, vol. 5, Article no: e492, pp. 1-10, doi: 10.1038/tp.2014.131.

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Title N-Acetylcysteine improves mitochondrial function and ameliorates behavioral deficits in the R6/1 mouse model of Huntington's disease
Author(s) Wright, D. J.
Renoir, T.
Smith, Z. M.
Frazier, A. E.
Francis, P. S.ORCID iD for Francis, P. S. orcid.org/0000-0003-4165-6922
Thorburn, D. R.
McGee, S. L.
Hannan, A. J.
Gray, L. J.
Journal name Translational psychiatry
Volume number 5
Season Article no: e492
Start page 1
End page 10
Total pages 10
Publisher Nature Publishing Group
Place of publication New York, N. Y.
Publication date 2015
ISSN 2158-3188
Keyword(s) Acetylcysteine
Animals
Behavior, Animal
Brain
Disease Models, Animal
Disease Progression
Excitatory Amino Acid Transporter 2
Free Radical Scavengers
Gait
Huntington Disease
Mice
Mice, Transgenic
Mitochondria
Motpr Activity
Organ Size
Oxidative Stress
Summary 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.
Language eng
DOI 10.1038/tp.2014.131
Field of Research 170101 Biological Psychology (Neuropsychology, Psychopharmacology, Physiological Psychology)
Socio Economic Objective 970106 Expanding Knowledge in the Biological Sciences
HERDC Research category C1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2015, Nature Publishing Group
Persistent URL http://hdl.handle.net/10536/DRO/DU:30071649

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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.