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Early alterations of brain cellular energy homeostasis in Huntington disease models.
Mochel-F; Durant-B; Meng-X; O'Callaghan-J; Yu-H; Brouillet-E; Wheeler-VC; Humbert-S; Schiffmann-R; Durr-A
J Biol Chem 2012 Jan; 287(2):1361-1370
Brain energy deficit has been a suggested cause of Huntington disease (HD), but ATP depletion has not reliably been shown in preclinical models, possibly because of the immediate post-mortem changes in cellular energy metabolism. To examine a potential role of a low energy state in HD, we measured, for the first time in a neurodegenerative model, brain levels of high energy phosphates using microwave fixation, which instantaneously inactivates brain enzymatic activities and preserves in vivo levels of analytes. We studied HD transgenic R6/2 mice at ages 4, 8, and 12 weeks. We found significantly increased creatine and phosphocreatine, present as early as 4 weeks for phosphocreatine, preceding motor system deficits and decreased ATP levels in striatum, hippocampus, and frontal cortex of R6/2 mice. ATP and phosphocreatine concentrations were inversely correlated with the number of CAG repeats. Conversely, in mice injected with 3-nitroproprionic acid, an acute model of brain energy deficit, both ATP and phosphocreatine were significantly reduced. Increased creatine and phosphocreatine in R6/2 mice was associated with decreased guanidinoacetate N-methyltransferase and creatine kinase, both at the protein and RNA levels, and increased phosphorylated AMP-dependent protein kinase (pAMPK) over AMPK ratio. In addition, in 4-month-old knock-in Hdh(Q111/+) mice, the earliest metabolic alterations consisted of increased phosphocreatine in the frontal cortex and increased the pAMPK/AMPK ratio. Altogether, this study provides the first direct evidence of chronic alteration in homeostasis of high energy phosphates in HD models in the earliest stages of the disease, indicating possible reduced utilization of the brain phosphocreatine pool.
Behavior; Brain-disorders; Muscle-function; Laboratory-animals; Cerebrovascular-system; Cerebrovascular-system-disorders; Cell-biology; Cell-function; Cellular-function; Metabolism; Models; Adenosines; Nucleotides; Phosphates; Author Keywords: Brain Metabolism; Creatine; Energy Metabolism; Huntington Disease; Polyglutamine Disease; Microwave; Phosphocreatine
Fanny Mochel, Brain and Spine Institute, INSERMUMRS975, Hôpital de La Salpêtrière, 75013 Paris, France
Issue of Publication
Journal of Biological Chemistry
TX; WV; MA