Parkinsons Disease - Redox Mechanisms

Abstract

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 lost. Dopaminergic neurons appear to die by a process of apoptosis that is induced by oxidative stress. Oxygen radicals abstract hydrogen from DNA forming DNA radicals that lead to DNA fragmentation, activation of DNA protective mechanisms, NAD depletion and apoptosis. Oxygen radicals can be formed in dopaminergic neurons by redox cycling of MPP+, the active metabolite of MPTP. This redox cycling mechanism involves the reduction of MPP+ by a number of enzymes, especially flavin containing enzymes, some of which are found in mitochondria. Tyrosine hydroxylase is present in all dopaminergic neurons and is responsible for the synthesis of dopamine. However, tyrosine hydroxylase can form oxygen radicals in a redox mechanism involving its cofactor, tetrahydrobiopterin. Dopamine may be oxidized by monoamine oxidase to form oxygen radicals and 3,4-dihydroxyphenylacetaldehyde. This aldehyde may be 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 dehydrogenase will be discussed. Possible clinical applications of these mechanisms will be briefly presented.

Vesicular monoamine transporter 2: Role as a novel target for drug development

“…[17][18][19][20][21] In this regard, DA may play a role as an endogenous toxin, since the normal metabolism of DA produces hydrogen peroxide as a byproduct, and the formation of DA-associated reactive oxygen species may contribute to the loss of nigrostriatal DA neurons. 22 Accordingly, pharmacologically enhancing DA sequestration by VMAT2, and thus preventing the oxidation of DA in the cytoplasm, may be a strategy for treatment of Parkinson ' s disease.…”

Investigations of differences in iron oxidation state inside single neurons from substantia nigra of Parkinson’s disease and control patients using the micro-XANES technique

“…The most characteristic feature of this disorder is the loss of neuromelanin (NM) rich neurons and the presence of Lewy bodies in the area of substantia nigra (SN) of the midbrain [1][2][3][4][5]. The causes of cellular loss are enigmatic in most individuals [1].…”

“…The causes of cellular loss are enigmatic in most individuals [1]. However, one of the leading hypotheses suggests that oxidative stress triggers a cascade of events resulting ultimately in the death of nerve cells [2][3][4][5].…”

Biological functions of selenium and its potential influence on Parkinson's disease

“…In dopaminergic cells, normal dopamine metabolism involving the tyrosine hydroxylase enzyme is responsible for producing oxygen radicals that damage biomolecule cells (Adams Jr et al 2001). This fact helps to explain the high oxidative stress generated in the dopaminergic neurons.…”