Dr. Marcy MacDonald with CAG repeats

The HD CAG Repeat Implicates a Dominant Property of Huntingtin in Mitochondrial Energy Metabolism.

Seong, Ivanova, Lee, Choo, Fossale, Anderson, Gusella, Laramie, Myers RH, Lesort M, Macdonald ME

The expanded HD CAG repeat that causes Huntington's disease (HD) encodes a polyglutamine tract in huntingtin that first targets the death of medium spiny striatal neurons. Mitochondrial energetics, related to N-methyl-D-aspartate (NMDA) Ca(2+)-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 STHdh(Q111) 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 Ca(2+)-influx through NMDA receptors that, when blocked, resulted in increased cellular [ATP/ADP]. We then evaluated [ATP/ADP] in forty 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 the HD range. Thus, the polyglutamine tract in huntingtin appears to regulate mitochondrial ADP-phosphorylation in a Ca(2+)-dependent process that fulfills the genetic criteria for the HD trigger of pathogenesis, and it thereby determines a fundamental biological parameter - cellular energy status, that 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 be tested as a potential physiological modifier in both health and disease.