HD CAG repeat implicates a dominant property of huntingtin in mitochondrial energy metabolism.
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.
Seong
Ihn Sik
IS
Molecular Neurogenetics UNIT, Center for Human Genetic Research, Massachusetts General Hospital, Richard B. Simches Research Center, Boston, MA 02114, USA.
Ivanova
Elena
E
Lee
Jong-Min
JM
Choo
Yeun Su
YS
Fossale
Elisa
E
Anderson
MaryAnne
M
Gusella
James F
JF
Laramie
Jason M
JM
Myers
Richard H
RH
Lesort
Mathieu
M
MacDonald
Marcy E
ME
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
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