Creatine Increases Survival and Delays Motor Symptoms in a Transgenic Animal Model of Huntington's Disease

Andreassen, Ole A.; Dedeoglu, Alpaslan; Ferrante, Robert J.; Jenkins, Bruce G.; Ferrante, Kimberly L.; Thomas, Melissa K.; Friedlich, Allan L.; Browne, Susan; Schilling, Gabriele; Borchelt, David R.; Hersch, Steven M.; Ross, Christopher A.; Beal, M. Flint

doi:10.1006/nbdi.2001.0406

Cited by 278 publications

(178 citation statements)

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“…These decreases in NAA occurred in the absence of any neuronal cell death. Also, dietary creatine supplementation significantly improved survival, slowed development of brain atrophy and delayed decreases in NAA (Andreassen et al, 2001;Ferrante et al, 2000). These results also indicate that the levels of NAA in the brain reflect the health of neurons and are a reliable marker for monitoring neuronal energy impairment and dysfunction.…”

Section: Impairments In Energy Metabolism Decrease Naa Levels In Brainmentioning

confidence: 65%

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

Moffett

Ross

Arun

et al. 2007

Progress in Neurobiology

1,230

1,126

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The brain is unique among organs in many respects, including its mechanisms of lipid synthesis and energy production. The nervous system-specific metabolite N-acetylaspartate (NAA), which is synthesized from aspartate and acetyl-coenzyme A in neurons, appears to be a key link in these distinct biochemical features of CNS metabolism. During early postnatal CNS development, the expression of lipogenic enzymes in oligodendrocytes, including the NAA-degrading enzyme aspartoacylase (ASPA), is increased along with increased NAA production in neurons. NAA is transported from neurons to the cytoplasm of oligodendrocytes, where ASPA cleaves the acetate moiety for use in fatty acid and steroid synthesis. The fatty acids and steroids produced then go on to be used as building blocks for myelin lipid synthesis. Mutations in the gene for ASPA result in the fatal leukodystrophy Canavan disease, for which there is currently no effective treatment. Once postnatal myelination is completed, NAA may continue to be involved in myelin lipid turnover in adults, but it also appears to adopt other roles, including a bioenergetic role in neuronal mitochondria. NAA and ATP metabolism appear to be linked indirectly, whereby acetylation of aspartate may facilitate its removal from neuronal mitochondria, thus favoring conversion of glutamate to alpha ketoglutarate which can enter the tricarboxylic acid cycle for energy production. In its role as a mechanism for enhancing mitochondrial energy production from glutamate, NAA is in a key position to act as a magnetic resonance spectroscopy marker for neuronal health, viability and number. Evidence suggests that NAA is a direct precursor for the enzymatic synthesis of the neuron specific dipeptide N-acetylaspartylglutamate, the most concentrated neuropeptide in the human brain. Other proposed roles for NAA include neuronal osmoregulation and axon-glial signaling. We propose that NAA may also be involved in brain nitrogen balance. Further research will be required to more fully understand the biochemical functions served by NAA in CNS development and activity, and additional functions are likely to be discovered.

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Section: Impairments In Energy Metabolism Decrease Naa Levels In Brainmentioning

confidence: 65%

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

Moffett

Ross

Arun

et al. 2007

Progress in Neurobiology

1,230

1,126

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“…The beneficial effects of creatine seem to be directly related with an increase in striatal ATP levels (Dedeoglu et al, 2003), and an overall improvement of the metabolic state of R6/2 mice. Dietary creatine supplementation was also reported to have similar beneficial effects in another transgenic mouse model of HD (N171-82Q mice) (Andreassen et al, 2001a). However, the effects of creatine in these HD mouse models could not be reproduced in HD patients.…”

Section: Energy Supplementation and Rescue Of Metabolic Impairmentmentioning

confidence: 90%

The R6 lines of transgenic mice: A model for screening new therapies for Huntington's disease

Gil

Rego

2009

Brain Research Reviews

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Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by an expanded CAG repeat in the HD gene that results in cortical and striatal degeneration, and mutant huntingtin aggregation. Current treatments are unsatisfactory. R6 transgenic mice replicate many features of the human condition, show early onset of symptoms and fast disease progression, being one of the most used models for therapy screening. Here we review the therapies that have been tested in these mice: environmental enrichment, inhibition of histone deacetylation and methylation, inhibition of misfolding and oligomerization, transglutaminase inhibition, rescue of metabolic impairment, amelioration of the diabetic phenotype, use of antioxidants, inhibition of excitotoxicity, caspase inhibition, transplantation, genetic manipulations, and restoration of neurogenesis. Although many of these treatments were beneficial in R6 mice, they may not be as effective in HD patients, and thus the search for a combination of therapies that will rescue the human condition continues.

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“…Similarly, reduced mitochondrial activity has been observed in at least one genetic mouse model of HD (16), and enhancement of electron transport by coenzyme Q10 is effective in genetic models (17)(18)(19)(20). HD patients also display increased ROS production in red blood cells and the striatum (21-24), which is reflected in in vitro and genetic mouse models of HD (18,(25)(26)(27).Complex II inhibitors generate ROS (26, 27) as a direct consequence of disruption of the electron transport chain and excitotoxicity by means of calcium influx through the N-methyl-D-aspartate receptor (28-30). Additionally, the high concentration of striatal dopamine may contribute to ROS production and exacerbate the damage caused by complex II inhibition (31).…”

mentioning

confidence: 89%

Protection from mitochondrial complex II inhibitionin vitroandin vivoby Nrf2-mediated transcription

Calkins

Jakel

Johnson

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

239

206

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Complex II inhibitors 3-nitropropionic acid (3NP) and malonate cause striatal damage reminiscent of Huntington's disease and have been shown to involve oxidative stress in their pathogenesis. Because nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent transcriptional activation by means of the antioxidant response element is known to coordinate the up-regulation of cytoprotective genes involved in combating oxidative stress, we investigated the significance of Nrf2 in complex II-induced toxicity. We found that Nrf2-deficient cells and Nrf2 knockout mice are significantly more vulnerable to malonate and 3NP and demonstrate increased antioxidant response element (ARE)-regulated transcription mediated by astrocytes. Furthermore, ARE preactivation by means of intrastriatal transplantation of Nrf2-overexpressing astrocytes before lesioning conferred dramatic protection against complex II inhibition. These observations implicate Nrf2 as an essential inducible factor in the protection against complex II inhibitor-mediated neurotoxicity. These data also introduce Nrf2-mediated ARE transcription as a potential target of preventative therapy in neurodegenerative disorders such as Huntington's disease.3-nitropropionic acid ͉ antioxidant response element ͉ astrocytes ͉ malonate M itochondrial complex II inhibition with 3-nitropropionic acid (3NP) or malonate produces a characteristic striatal degeneration similar to that seen in Huntington's disease (HD) (1, 2). HD is an autosomal dominant neurodegenerative disorder that results from a polyglutamine repeat expansion in the first exon of the huntingtin gene (3). Hallmarks of the genetic disease include severe degeneration of striatal medium spiny neurons and progressive choreiform movements (4, 5). Similar behavioral deficits and selective damage to the medium spiny neurons of the striatum with sparing of the aspiny neurons are seen after complex II inhibition (6-10).Furthermore, there is developing evidence that HD pathogenesis involves mitochondrial dysfunction, excitotoxicity, and subsequent reactive oxygen species (ROS) production (11-13). Mitochondrial deficiencies, including reduced overall respiration and reduced activities of complex II, III, and IV, have been measured in the striatum of postmortem HD brains (14,15). Similarly, reduced mitochondrial activity has been observed in at least one genetic mouse model of HD (16), and enhancement of electron transport by coenzyme Q10 is effective in genetic models (17)(18)(19)(20). HD patients also display increased ROS production in red blood cells and the striatum (21-24), which is reflected in in vitro and genetic mouse models of HD (18,(25)(26)(27).Complex II inhibitors generate ROS (26, 27) as a direct consequence of disruption of the electron transport chain and excitotoxicity by means of calcium influx through the N-methyl-D-aspartate receptor (28-30). Additionally, the high concentration of striatal dopamine may contribute to ROS production and exacerbate the damage caused by complex II inhibition (31). Stri...

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Creatine Increases Survival and Delays Motor Symptoms in a Transgenic Animal Model of Huntington's Disease

Cited by 278 publications

References 45 publications

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

The R6 lines of transgenic mice: A model for screening new therapies for Huntington's disease

Protection from mitochondrial complex II inhibitionin vitroandin vivoby Nrf2-mediated transcription

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