Access Type

Open Access Dissertation

Date of Award

January 2021

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Biological Sciences

First Advisor

David Njus

Abstract

Both Parkinson’s disease and manganism (a condition caused by chronic exposure to excessive levels of manganese) affect the extrapyramidal system of the brain, disrupt dopaminergic signaling and cause similar motor symptoms. While there is no physiological explanation for the susceptibility of dopamine-rich regions of the brain in both disorders, dopamine itself is a likely candidate. Dopamine can undergo both enzymatic and spontaneous oxidation, and the principal product of dopamine oxidation in vivo is cysteinyl dopamine. We demonstrate here that hypochlorous acid, which is produced in the brain by the enzyme myeloperoxidase, converts cysteinyl dopamine into a neurotoxic dihydrobenzothiazine, DHBT-1, that is associated with the degeneration of dopaminergic neurons in Parkinson’s disease. We also report here the formation of a novel class of compounds, dopathiazines (DTZ), that are also produced by the reaction of cysteinyl dopamine with hypochlorite. Two such dopathiazines, DTZ-1 and DTZ-2, undergo manganese-stimulated redox cycling activity, suggesting that they may exacerbate the manganese-dependent oxidative stress that is observed in manganism. DTZ-1 is also formed only when cysteinyl dopamine is exposed to hypochlorous acid in the presence of manganese, and this may account for the neurological selectivity of manganism. We suggest that naturally occurring dopamine-thiol adducts such as cysteinyl dopamine are converted into neurotoxic compounds identical or similar to DHBT-1 and Mn-complexing compounds identical or similar to DTZ-1 and DTZ-2. The formation of these compounds requires hypochlorous acid and may be prevented by taurine, which is an effective scavenger of hypochlorite, indicating that taurine can be potentially therapeutic to both disorders.

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