Research ReportUp-regulation of the isoenzymes MAO-A and MAO-B in the human basal ganglia and pons in Huntington's disease revealed by quantitative enzyme radioautography

Huntington's disease (HD) is a rare genetic disease associated with the degeneration of GABAergic striatal projection neurons in the basal ganglia leading to movement disorders with behavioral symptoms for which there is presently no therapy. Abnormally high levels of monoamine oxidase (MAO) activity, which are potentially linked to cytotoxic free radical formation, are known to occur during aging and in neurodegenerative disorders (MAO-B is markedly increased in plaque-associated astrocytes in Alzheimer's disease). We therefore measured, with anatomical resolution, MAO-A and -B activities in 5 cases of HD (severity grades 1-3) and age-matched controls by quantitative enzyme radioautography using radiolabeled enzyme inhibitors 3H-Ro 41-1049 and 3H-lazabemide, respectively, as high-affinity ligands in vitro. MAO-A was increased significantly (ca. 50%; p < 0.01) in the putamen and substantia nigra pars compacta of the basal ganglia and in the pons. Higher increases in MAO-B (75%-200%; p < 0.01) occurred in the putamen, ventral striatum, globus pallidus externus and internus of the basal ganglia and in the insular cortex. The increased enzyme levels (especially of MAO-B) seemed to correlate with the grade of disease severity. We conclude that MAO increases in those regions of HD brains which are known to undergo neurodegeneration accompanied by glioses. Whether or not this increased enzyme activity is a cause or effect of the resulting loss of the GABAergic projection neurons in HD is yet to be clarified. Moreover, it remains to be seen if selective enzyme inhibitors have therapeutic utility in the treatment of HD by reducing oxidative stress locally.

Research Highlights►Quantitative enzyme radioautography reveals increased MAO-A and -B in Huntington's disease. ► Its anatomical resolution allows discrete brain regions to be identified. ►MAO-B (≫ MAO-A) increases in striatum, globus pallidus and substantia nigra. ►The changes correlate with the principal sites of pathology in the disease. ►MAO inhibitors, by reducing oxidative stress locally, might have therapeutic utility.