title: 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.
authors.affiliation: 1] Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia [2] School of Medicine, Faculty of Health, Deakin University, Geelong, VIC, Australia.
authors.forename: D J
authors.initials: DJ
authors.lastname: Wright
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
authors.forename: T
authors.initials: T
authors.lastname: Renoir
authors.affiliation: Centre for Chemistry and Biotechnology, Faculty of Science, Engineering and Built Environment, Deakin University, Geelong, VIC, Australia.
authors.forename: Z M
authors.initials: ZM
authors.lastname: Smith
authors.affiliation: 1] Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, VIC, Australia [2] Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia.
authors.forename: A E
authors.initials: AE
authors.lastname: Frazier
authors.affiliation: Centre for Chemistry and Biotechnology, Faculty of Science, Engineering and Built Environment, Deakin University, Geelong, VIC, Australia.
authors.forename: P S
authors.initials: PS
authors.lastname: Francis
authors.affiliation: 1] Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, VIC, Australia [2] Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia [3] Victorian Clinical Genetics Services, Royal Children's Hospital, Melbourne, VIC, Australia.
authors.forename: D R
authors.initials: DR
authors.lastname: Thorburn
authors.affiliation: 1] Metabolic Remodelling Laboratory, Metabolic Research Unit, School of Medicine, Deakin University, Geelong, VIC, Australia [2] Division of Cell Signalling and Metabolism, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia.
authors.forename: S L
authors.initials: SL
authors.lastname: McGee
authors.affiliation: 1] Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia [2] Department of Anatomy and Neuroscience, University of Melbourne, Parkville, VIC, Australia.
authors.forename: A J
authors.initials: AJ
authors.lastname: Hannan
authors.affiliation: 1] Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia [2] School of Medicine, Faculty of Health, Deakin University, Geelong, VIC, Australia.
authors.forename: L J
authors.initials: LJ
authors.lastname: Gray
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D027342:Excitatory Amino Acid Transporter 2 / Q000187:drug effects / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005684:Gait / Q000187:drug effects; D006816:Huntington Disease / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D009929:Organ Size; D018384:Oxidative Stress / Q000187:drug effects*
chemical_list: D027342:Excitatory Amino Acid Transporter 2; D016166:Free Radical Scavengers; C493396:Slc1a2 protein, mouse; D000111:Acetylcysteine