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.

Calcium Homeostasis and Mitochondrial Dysfunction in Striatal Neurons of Huntington Disease

“…They have indeed been found in the brain of HD patients (6) and in the striatal and other cells of animal HD models (7)(8)(9). The defective mitochondrial component has been suggested to be complex II of the respiratory chain.…”

Brain urea increase is an early Huntington’s disease pathogenic event observed in a prodromal transgenic sheep model and HD cases

“…HD patient-derived cell lines have identified CAG repeat length correlated with changes in the ratio of ATP to ADP (16), implying a direct role of huntingtin in metabolic regulation. It is unclear how the HD mutation causes these metabolic changes, particularly in the initiating stages of the disease.…”

Preventing polyglutamine-induced activation of c-Jun delays neuronal dysfunction in a mouse model of SCA7 retinopathy

“…Protein misfolding is expected to induce cellular stress response, including the activation of the JNK/cJun/AP-1 signaling pathway (Sherman and Goldberg, 2001;Nishitoh et al, 2002;Merienne et al, 2003;Garcia et al, 2004). In addition, excitotoxicity, energy impairment, defects in calcium homeostasis and oxidative stress, which are also stress responses associated with activation of JNK/AP-1 pathway, are implicated in polyQ expansion diseases (Browne et al, 1997;Lin et al, 2000;Wyttenbach et al, 2002;Li et al, 2003;Seong et al, 2005).…”