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Cells. 2019 Jan 16;8(1). pii: E59. doi: 10.3390/cells8010059.

Are Proteinopathy and Oxidative Stress Two Sides of the Same Coin?

Author information

1
Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. nihar.mehta@nih.gov.
2
Department of Biological Sciences, Wayne State University, Detroit, MI 48202, USA. praneet.marwah@wayne.edu.
3
Department of Biological Sciences, Wayne State University, Detroit, MI 48202, USA. dnjus@wayne.edu.

Abstract

Parkinson's disease, like other neurodegenerative diseases, exhibits two common features: Proteinopathy and oxidative stress, leading to protein aggregation and mitochondrial damage respectively. Because both protein aggregates and dysfunctional mitochondria are eliminated by autophagy, we suggest that inadequate clearance may couple the two phenomena. If a neuron's autophagy machinery is overwhelmed, whether by excessive oxidative stress or by excessive protein aggregation, protein aggregates and dysfunctional mitochondria will both accumulate. Parkinson's disease may provide a unique window into this because there is evidence that both sides contribute. Mutations amplifying the aggregation of α-synuclein are associated with Parkinson's disease. Likewise, mutations in Parkin and PINK1, proteins involved in mitophagy, suggest that impaired mitochondrial clearance is also a contributing factor. Many have suggested that dopamine oxidation products lead to oxidative stress accounting for the dopaminergic selectivity of the disease. We have presented evidence for the specific involvement of hypochlorite-oxidized cysteinyl-dopamine (HOCD), a redox-cycling benzothiazine derivative. While toxins like 6-hydroxydopamine and 1-methyl-4-phenyl pyridinium (MPP+) have been used to study mitochondrial involvement in Parkinson's disease, HOCD may provide a more physiologically relevant approach. Understanding the role of mitochondrial dysfunction and oxidative stress in Parkinson's disease and their relation to α-synuclein proteinopathy is important to gain a full picture of the cause, especially for the great majority of cases which are idiopathic.

KEYWORDS:

Parkinson’s disease; autophagy; cysteinyl-dopamine; hypochlorite; oxidative stress; redox cycling

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