From quinones to mitochondria: exploring the ‘complex’ progression of oxidative stress in Parkinson’s Disease
Introduction. Parkinson’s Disease (PD) is a long-term neurodegenerative disease and progressive movement disorder of the CNS due largely to neuronal death of the substantia nigra region of the midbrain and subsequent loss of dopamine production. Although the cause is largely unknown, it is suggested that oxidative stress, free radical production, and mitochondrial dysfunction are upstream initiating events leading to PD. This project focuses on providing a potential mechanism through which the direct oxidation of dopamine leads to downstream impairments in protein function and uncontrolled neuroinflammation. Loss of function in mitochondrial complex I is observed as a common denominator to each of these lesions. Methods. The independent studies considered in this project involved primarily mice and human cell models. The direct effects of DA quinones on mitochondria were demonstrated in mice pheochromocytoma (PC12) cell line. The effects of quinones on DJ-1 and a-syn were observed in human SH-SY5Y neuroblastoma cells using radioactivity assays for tagging residues and small-angle x-ray scattering (SAXS) to study oligomeric characteristics, respectively 1,3. Results. In the absence of TH, tyrosinase rapidly oxidizes excess amounts of cytosolic DA and L-DOPA, leading to the formation of electron-deficient quinones. The direct effects of DA quinones on mitochondria involve inhibition of respiratory chain complexes, specifically complex I. The indirect effects of DA quinones are observed in protein dysfunction and an extensive neuroinflammatory response. Normally functioning DJ-1 is shown to directly bind to NDUFA4 and ND1, subunits of complex I that are localized in the mitochondrial inner membrane 1. Furthermore, DJ-1 regulates astrocyte-mediated neuroinflammation through iNOS induction via the p38MAPK pathway 6. Covalent modifications by quinones included adduct formation on two cysteine residues of DJ-1 leading to severe structural perturbations. Loss of DJ-1 function contributes to neurodegeneration by deregulation of the astrocytic iNOS and COX-2, leading to the formation of excessive, potentially neurotoxic amounts of NO and prostaglandins, respectively 9. Normally functioning a-synuclein is involved in maintaining mitochondrial complex I membrane potential 2. DA quinones couple the Tyr and Lys residues on a-synuclein and oxidize the methionine residues at the terminal ends to inhibit formation of the B-sheet structure found in functional forms 3. Microglial activation, TNF-α, and TLR expression were selectively increased in the striatum and substantia nigra of mice with improperly folded a-synuclein, suggesting a compensatory neuroinflammatory response 5. Finally, neuroinflammation is characteristically shown to cause mitochondrial dysfunction. Conclusions. Determining the upstream cause of this mitochondrial dysfunction is critical in the development of effective therapies for PD. This proposed mechanism is unique because it accounts for dopamine quinones directly accounting for familial and sporadic cases of PD via the involvement of DJ-1 and a-synuclein, respectively. Furthermore, it bridges each downstream effect from quinone formation to mitochondrial complex I dysfunction. This may provide a new outlook for PD therapies and re-evaluation of current ones, such as L-DOPA administration which may lead to DA buildup. For this reason, consideration is being given to neuroprotective therapies involving inorganic and organic agents 4,11.
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