title: HD CAG repeat implicates a dominant property of huntingtin in mitochondrial energy metabolism.
abstract: The 'expanded' HD CAG repeat that causes Huntington's disease (HD) encodes a polyglutamine tract in huntingtin, which first targets the death of medium-sized spiny striatal neurons. Mitochondrial energetics, related to N-methyl-d-aspartate (NMDA) Ca2+-signaling, has long been implicated in this neuronal specificity, implying an integral role for huntingtin in mitochondrial energy metabolism. As a genetic test of this hypothesis, we have looked for a relationship between the length of the HD CAG repeat, expressed in endogenous huntingtin, and mitochondrial ATP production. In STHdhQ111 knock-in striatal cells, a juvenile onset HD CAG repeat was associated with low mitochondrial ATP and decreased mitochondrial ADP-uptake. This metabolic inhibition was associated with enhanced Ca2+-influx through NMDA receptors, which when blocked resulted in increased cellular [ATP/ADP]. We then evaluated [ATP/ADP] in 40 human lymphoblastoid cell lines, bearing non-HD CAG lengths (9-34 units) or HD-causing alleles (35-70 units). This analysis revealed an inverse association with the longer of the two allelic HD CAG repeats in both the non-HD and HD ranges. Thus, the polyglutamine tract in huntingtin appears to regulate mitochondrial ADP-phosphorylation in a Ca2+-dependent process that fulfills the genetic criteria for the HD trigger of pathogenesis, and it thereby determines a fundamental biological parameter--cellular energy status, which may contribute to the exquisite vulnerability of striatal neurons in HD. Moreover, the evidence that this polymorphism can determine energy status in the non-HD range suggests that it should be tested as a potential physiological modifier in both health and disease.
authors.affiliation: Molecular Neurogenetics UNIT, Center for Human Genetic Research, Massachusetts General Hospital, Richard B. Simches Research Center, Boston, MA 02114, USA.
authors.forename: Ihn Sik
authors.initials: IS
authors.lastname: Seong
authors.forename: Elena
authors.initials: E
authors.lastname: Ivanova
authors.forename: Jong-Min
authors.initials: JM
authors.lastname: Lee
authors.forename: Yeun Su
authors.initials: YS
authors.lastname: Choo
authors.forename: Elisa
authors.initials: E
authors.lastname: Fossale
authors.forename: MaryAnne
authors.initials: M
authors.lastname: Anderson
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
authors.forename: Jason M
authors.initials: JM
authors.lastname: Laramie
authors.forename: Richard H
authors.initials: RH
authors.lastname: Myers
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lesort
authors.forename: Marcy E
authors.initials: ME
authors.lastname: MacDonald
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D017668:Age of Onset; D000483:Alleles; D020013:Calcium Signaling; D002478:Cells, Cultured; D042622:DNA Repeat Expansion; D004734:Energy Metabolism / Q000235:genetics; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010455:Peptides / Q000235:genetics; D010766:Phosphorylation; D011110:Polymorphism, Genetic; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D016194:Receptors, N-Methyl-D-Aspartate; C097188:polyglutamine; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate