Parkinson's disease - Redox mechanisms

Parkinson's disease occurs in 1% of people over the age of 65 when about 60 % of the dopaminergic neurons in the substantia nigra of the midbrain are l ost. Dopaminergic neurons appear to die by a process of apoptosis that is i nduced by oxidative stress. Oxygen radicals abstract hydrogen from DNA form ing DNA radicals that lead to DNA fragmentation, activation of DNA protecti ve mechanisms, NAD depletion and apoptosis. Oxygen radicals can be formed i n dopaminergic neurons by redox cycling of MPP+, the active metabolite of M PTP. This redox cycling mechanism involves the reduction of MPP+ by a numbe r of enzymes, especially flavin containing enzymes, some of which are found in mitochondria. Tyrosine hydroxylase is present in all dopaminergic neuro ns and is responsible for the synthesis of dopamine. However, tyrosine hydr oxylase can form oxygen radicals in a redox mechanism involving its cofacto r, tetrahydrobiopterin. Dopamine may be oxidized by monoamine oxidase to fo rm oxygen radicals and 3,4-dihydroxyphenylacetaldehyde. This aldehyde may b e oxidized by aldehyde dehydrogenase with the formation of oxygen radicals and 3,4-dihydroxyphenylacetic acid. The redox mechanisms of oxygen radical formation by MPTP, tyrosine hydroxylase, monoamine oxidase and aldehyde deh ydrogenase will be discussed. Possible clinical applications of these mecha nisms will be briefly presented.