Mitochondria, monoamine oxidase B and Parkinson’s disease

The cause of cell death in Parkinson’s disease (PD) remains unclear but it is multifactorial with a complex interaction between a range of pathogenic mechanisms. However, alterations in mitochondrial function have been clearly linked to nigral dopaminergic loss in sporadic PD and to the effects of gene mutations in familial forms of the illness. These may underlie the onset of oxidative and nitrative stress, a failure of protein degradation and apoptotic degeneration of dopaminergic cells in PD. Perhaps importantly, monoamine oxidase B (MAO-B) is located in the mitochondrial wall and plays a significant role in dopamine degradation in PD. This can explain the symptomatic actions of MAO-B inhibitors, such as selegiline and rasagiline on motor symptoms of PD. However, both selegiline and rasagiline also are associated with neuroprotective and/or disease modifying activities. The second generation MAO-B inhibitor, rasagiline can prevent multiple pathways that lead to apoptotic cell death and it is effective in in vitro and in vivo models of neuronal degeneration. However, there may be contributions from its major metabolite, aminoindan and non-MAO-B mediated actions on mitochondria may also contribute to these effects. It is important to determine whether these actions contribute to the possible disease modifying effect of MAO-B inhibitors in PD in man.