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Mutant and wild-type α-synuclein interact with mitochondrial cytochrome C oxidase

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Abstract

α-synuclein, a presynaptic protein, was found to be the major component in the Lewy bodies (LB) in both inherited and sporadic Parkinson’s disease (PD). Furthermore, rare mutations of α-synuclein cause autosomal-dominant PD. However, it is unknown how α-synuclein is involved in the pathogenesis of nigral degeneration in PD. In this study, we examine the protein-protein interactions of wild-type and mutant (A53T) α-synuclein with adult human brain cDNA expression library using the yeast two-hybrid technique. We found that both normal and mutant α-synuclein specifically interact with the mitochondrial complex IV enzyme, cytochrome C oxidase (COX). Wild-type and mutant α-synuclein genes were further fused with c-Myc tag and translated in rabbit reticulocyte lysate. Using anti-c-Myc antibody, we demonstrated that both wild-type and mutant α-synuclein, coimmunoprecipitated with COX. We also showed that potassium cyanide, a selective COX inhibitor, synergistically enhanced the sensitivity of SH-SY5Y neuroblastoma cells to dopamine-induced cell death. In conclusion, we found specific protein-protein interactions of α-synuclein, a major LB protein, to COX, a key enzyme of the mitochondrial respiratory system. This interaction suggests that α-synuclein aggregation may contribute to enhance the mitochondrial dysfunction, which might be a key factor in the pathogenesis of PD.

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Authors and Affiliations

  1. Felsenstein Medical Research Center, Department of Clinical Biochemistry, Sackler School of Medicine, Tel-Aviv University, Israel

    Hanock Elkon, Eldad Melamed, Ilan Ziv, Anat Shirvan & Daniel Offen

  2. Department of Neurology, Rabin Medical Center, Petah-Tikva, Israel

    Hanock Elkon, Eldad Melamed, Ilan Ziv, Anat Shirvan & Daniel Offen

  3. Faculty of Life Sciences Bar-Ilan University, Ramat-Gan, Israel

    Jermy Don

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  1. Hanock Elkon
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  2. Jermy Don
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  3. Eldad Melamed
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  4. Ilan Ziv
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  6. Daniel Offen
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Correspondence to Daniel Offen.

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Elkon, H., Don, J., Melamed, E. et al. Mutant and wild-type α-synuclein interact with mitochondrial cytochrome C oxidase. J Mol Neurosci 18, 229–238 (2002). https://doi.org/10.1385/JMN:18:3:229

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  • DOI: https://doi.org/10.1385/JMN:18:3:229

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