title: Energy defects in Huntington's disease: Why "in vivo" evidence matters.
abstract: Huntington's disease (HD) is an inherited progressive neurodegenerative disorder associated with involuntary abnormal movements (chorea), cognitive deficits and psychiatric disturbances. The most striking neuropathological change in HD is the early atrophy of the striatum. While the disease progresses, other brain structures also degenerate, including the cerebral cortex. Changes are also seen outside the brain, in particular weight loss/cachexia despite high dietary intake. The disease is caused by an abnormal expansion of a CAG repeat in the gene encoding the huntingtin protein (Htt). This mutation leads to the expression of a poly-glutamine stretch that changes the biological functions of mutant Htt (mHtt). The mechanisms underlying neurodegeneration in HD are not totally elucidated. Here, we discuss recent results obtained in patients, animal and cellular models suggesting that early disturbance in energy metabolism at least in part associated with mitochondrial defects may play a central role, even though all data are not congruent, possibly because most findings were obtained in cell culture systems or using biochemical analyses of post mortem tissues from rodent models. Thus, we put a particular focus on brain imaging studies that could identify biomarkers of energy defects in vivo and would be of prime interest in preclinical and clinical trials testing the efficacy of new therapies targeting energy metabolism in HD.
authors.affiliation: CEA, DRF, I(2)BM, Molecular Imaging Research Center (MIRCen), F-92265, Fontenay-aux-Roses, France; CEA, CNRS, Paris-Sud University, Paris-Saclay University, UMR9199, Neurodegenerative Diseases Laboratory, F-92265, Fontenay-aux-Roses, France.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Liot
authors.affiliation: CEA, DRF, I(2)BM, Molecular Imaging Research Center (MIRCen), F-92265, Fontenay-aux-Roses, France; CEA, CNRS, Paris-Sud University, Paris-Saclay University, UMR9199, Neurodegenerative Diseases Laboratory, F-92265, Fontenay-aux-Roses, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Valette
authors.affiliation: CEA, DRF, I(2)BM, Molecular Imaging Research Center (MIRCen), F-92265, Fontenay-aux-Roses, France; CEA, CNRS, Paris-Sud University, Paris-Saclay University, UMR9199, Neurodegenerative Diseases Laboratory, F-92265, Fontenay-aux-Roses, France.
authors.forename: Jérémy
authors.initials: J
authors.lastname: Pépin
authors.affiliation: CEA, DRF, I(2)BM, Molecular Imaging Research Center (MIRCen), F-92265, Fontenay-aux-Roses, France; Institut National de la santé et de la recherche médicale (Inserm), UMS 27, F-92265, Fontenay-aux-Roses, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Flament
authors.affiliation: CEA, DRF, I(2)BM, Molecular Imaging Research Center (MIRCen), F-92265, Fontenay-aux-Roses, France; CEA, CNRS, Paris-Sud University, Paris-Saclay University, UMR9199, Neurodegenerative Diseases Laboratory, F-92265, Fontenay-aux-Roses, France. Electronic address: Emmanuel.brouillet@cea.fr.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Brouillet
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D004734:Energy Metabolism; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism
chemical_list: D002118:Calcium
keywords: Biomarker; Calcium; Energy metabolism; Excitotoxicity; Glutamate; Huntington's disease; Mitochondria; NMDA receptors; NMR; Spectroscopy