title: Early alterations of brain cellular energy homeostasis in Huntington disease models.
abstract: 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.
authors: INSERM UMR S975 and Assistance-Publique des Hôpitaux de Paris, Department of Genetics, Hôpital La Salpêtrière, 75013 Paris, France. fanny.mochel@upmc.fr
authors: Fanny
authors: F
authors: Mochel
authors: Brandon
authors: B
authors: Durant
authors: Xingli
authors: X
authors: Meng
authors: James
authors: J
authors: O'Callaghan
authors: Hua
authors: H
authors: Yu
authors: Emmanuel
authors: E
authors: Brouillet
authors: Vanessa C
authors: VC
authors: Wheeler
authors: Sandrine
authors: S
authors: Humbert
authors: Raphael
authors: R
authors: Schiffmann
authors: Alexandra
authors: A
authors: Durr
mesh_terms: D000255:Adenosine Triphosphate / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001923:Brain Chemistry; D003292:Convulsants / Q000494:pharmacology; D004195:Disease Models, Animal; D004734:Energy Metabolism; D005625:Frontal Lobe / Q000378:metabolism* / Q000473:pathology; D055879:Gene Knock-In Techniques; D050937:Guanidinoacetate N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009574:Nitro Compounds / Q000494:pharmacology; D010725:Phosphocreatine / Q000235:genetics / Q000378:metabolism*; D011422:Propionates / Q000494:pharmacology
chemical_list: D003292:Convulsants; D009419:Nerve Tissue Proteins; D009574:Nitro Compounds; D011422:Propionates; D010725:Phosphocreatine; D000255:Adenosine Triphosphate; C494507:Gamt protein, mouse; D050937:Guanidinoacetate N-Methyltransferase; C015392:3-nitropropionic acid