Nonlinear decrease over time in N-acetyl aspartate levels in the absence of neuronal loss and increases in glutamine and glucose in transgenic Huntington's disease mice

Mice transgenic for exon I of mutant huntingtin, with 141 CAG repeals, exhi bit a profound symptomatology characterized by weight loss, motor disorders , and early death. We performed longitudinal analysis of metabolite levels in these mice using NMR spectroscopy in vivo and in vitro. These mice exhib ited a large (53%), nonlinear drop in in vivo N-acetyl aspartate (NAA) leve ls over time, commencing at similar to 6 weeks of age, coincident with onse t of symptoms. These drops in NAA levels occurred in the absence of neurona l death as measured by postmortem Nissl staining and neuronal counting but in the presence of nuclear inclusion bodies. In addition to decreased NAA, these mice showed a large elevation of glucose in the brain (600%) consiste nt with a diabetic profile and elevations in blood glucose levels both befo re and after glucose loading. In vitro NMR analysis revealed significant in creases in glutamine (100%), taurine (95%) cholines (200%), and scyllo-inos itol (333%) and decreases in glutamate (24%) and succinate (47%). These res ults lead to two conclusions. NAA is reflective of the health of neurons an d thus is a noninvasive marker, with a temporal progression similar to nucl ear inclusion bodies and symptoms, of neuronal dysfunction in transgenic mi ce. Second, the presence of elevated glutamine is evidence of a profound me tabolic defect. We present arguments that the elevated glutamine results fr om a decrease in neuronal-glial glutamate-glutamine cycling and a decrease in glutaminase activity.