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Exp Neurol. 2015 Sep;271:13-24. doi: 10.1016/j.expneurol.2015.04.019. Epub 2015 May 6.

In vivo protein targets for increased quinoprotein adduct formation in aged substantia nigra.

Author information

1
Key Laboratory of Brain Functional Genomics (East China Normal University), Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics (East China Normal University), School of Life Sciences, East China Normal University, Shanghai, China. Electronic address: xiaoqsh2003@163.com.
2
Key Laboratory of Brain Functional Genomics (East China Normal University), Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics (East China Normal University), School of Life Sciences, East China Normal University, Shanghai, China.
3
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.
4
Shandong Provincial Research Center for Bioinformatic Engineering and Technique, Center for Advanced Study, Shandong University of Technology, Zibo, China.
5
Key Laboratory of Brain Functional Genomics (East China Normal University), Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics (East China Normal University), School of Life Sciences, East China Normal University, Shanghai, China; Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI, USA. Electronic address: jiyan.ma@vai.org.

Abstract

The selective vulnerability of dopaminergic neurons in the substantia nigra pars compacta in Parkinson's disease, a late age onset neurodegenerative disorder, indicates the involvement of dopamine metabolism in the pathogenesis. Dopamine oxidation produces dopamine o-quinone, which covalently modifies cysteinyl proteins forming quinoprotein adduct. Although quinoprotein formation correlates with increased dopaminergic neurotoxicity, the in vivo protein targets for quinone modification remain unclear. Using two-dimensional gel electrophoresis and nitroblue tetrazolium/glycinate redox-cycling staining, we compared quinoprotein adducts in the substantia nigra of 2- and 15-month old rats and for the first time identified the in vivo protein targets with increased quinone modification in aged substantia nigra. Interestingly, several key enzymes in energy metabolism and mitochondrial function were selectively modified by quinone during aging. In vitro analyses confirmed that two of identified enzymes, l-lactate dehydrogenase (LDH) and malate dehydrogenase (MDH), were readily conjugated by dopamine o-quinone, resulting in a significant reduction in enzyme activity. Since the proteomic approach to detect quinoprotein adducts represents a single analysis comparing pools of substantia nigra from young or old rats, these findings need to be verified in the future. Nonetheless, our results reveal that the enzymatic activity of LDH and MDH can be compromised by quinone modification, suggesting a role of energy metabolism impairment in the selective vulnerability of aged substantia nigra dopaminergic neurons in Parkinson's disease.

KEYWORDS:

Dopamine quinone; Energy metabolism; Parkinson's disease; Quinoprotein; Substantia nigra

PMID:
25956828
DOI:
10.1016/j.expneurol.2015.04.019
[Indexed for MEDLINE]

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