(11) MITOCHONDRIAL MONOAMINE OXIDASE AND NEURODEGENERATIVE DISORDERS

Andrea M. Cesura, Jÿrgen Gottowik, J. Grayson Richards, Pari Malherbe, Caroline Kuhn and Edilio Borroni
Pharmaceutical Division, Preclinical Research, Nervous System Diseases, F. Hoffmann- La Roche Ltd, CH-4070 Basel, Switzerland

The two forms of mitochondrial monoamine oxidase (flavin-containing, MAO), namely MAO-A and B are primarily responsible for the oxidative deamination of monoamine neurotransmitters. Reactive oxygen species (ROS) production by MAO, in particular the B isoform of the enzyme, has been claimed to play a relevant role in cerebral aging processes and in the pathogenesis of some neurological disorders, such as Parkinson's disease, Alzheimer's disease (AD) and Huntington's chorea. For instance, we and others have found that MAO-B appears to be highly overexpressed in astrocytes associated with senile plaques of AD brains. ROS derived from MAO-B overexpression may contribute to the development of mature amyloid plaques and exacerbate the cytotoxic effects of b-amyloid peptide. In addition, due to its mitochondrial location, MAO-mediated ROS production might induce damage to specific mitochondrial functions.

To gain insight into the role of MAO-B in brain oxidative stress, transgenic mice overexpressing human MAO-B in neurons were generated. In these animals, MAO-B overexpression was found to affect dopamine metabolism and its turnover rate was significantly increased in comparison to non-transgenic mice. Since substrate deamination by MAO-B is stoichiometrically linked to H2O2 production, the brains of MAO-B transgenic mice may be subjected to a chronic oxidative challenge. In support of this, we found that, in transgenic mice, the expression levels of brain L-ferritin mRNA increased by ~70% in comparison to non-transgenic littermates. Treatment with the dopamine precursor L-DOPA and benserazide, to provide more substrate for the enzyme, further increased L-ferritin mRNA expression in the brains of transgenic but not of control mice. Co-administration of the selective MAO-B inhibitor lazabemide prevented the increase in L-ferritin mRNA induced by L-DOPA/benserazide treatment. Since the control of iron homeostasis, through the regulation of the synthesis of ferritin isoforms, represents a primary antioxidant defence, these results provide in vivo evidence that cerebral MAO-B overexpression induces a typical response to oxidative stimuli. Further studies on aged animals will be instrumental for precisely assessing the possible contribution of MAO-B overexpression to cell and mitochondrial damage.