Parkin Somatic Mutations Link Melanoma and Parkinson's Disease

Lotan Levin; Shani Srour; Jared Gartner; Oxana Kapitansky; Nouar Qutob; Shani Dror; Tamar Golan; Roy Dayan; Ronen Brener; Tamar Ziv; Mehdi Khaled; Ora Schueler-Furman; Yardena Samuels; Carmit Levy

doi:10.1016/j.jgg.2016.05.005

Volume 43 Issue 6

Jun. 2016

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Article Navigation > Journal of Genetics and Genomics > 2016 > 43(6): 369-379

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Parkin Somatic Mutations Link Melanoma and Parkinson's Disease

doi: 10.1016/j.jgg.2016.05.005

a
Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
b
Surgery Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA
c
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel
d
Oncology Institute, Edith Wolfson Medical Center, Holon 5822012, Israel
e
Technion Smoler Proteomics Center, Faculty of Biology, Technion – Israel Institute of Technology, Haifa 32000, Israel
f
Institut Gustave Roussy, INSERM U753, Villejuif 94805, France
g
Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University, Jerusalem 91120, Israel

More Information

Corresponding author: E-mail address: carmitlevy@post.tau.ac.il (Carmit Levy)
Received Date: 2015-10-30
Accepted Date: 2016-05-12
Rev Recd Date: 2016-05-11

Available Online: 2016-05-13

Publish Date: 2016-06-20

Abstract

Abstract

Epidemiological studies suggest a direct link between melanoma and Parkinson's disease (PD); however, the underlying molecular basis is unknown. Since mutations in Parkin are the major driver of early-onset PD and Parkin was recently reported to play a role in cancer development, we hypothesized that Parkin links melanoma and PD. By analyzing whole exome/genome sequencing of Parkin from 246 melanoma patients, we identified five non-synonymous mutations, three synonymous mutations, and one splice region variant in Parkin in 3.6% of the samples. In vitro analysis showed that wild-type Parkin plays a tumor suppressive role in melanoma development resulting in cell-cycle arrest, reduction of metabolic activity, and apoptosis. Using a mass spectrometry-based analysis, we identified potential Parkin substrates in melanoma and generated a functional protein association network. The activity of mutated Parkin was assessed by protein structure modeling and examination of Parkin E3 ligase activity. The Parkin-E28K mutation impairs Parkin ubiquitination activity and abolishes its tumor suppressive effect. Taken together, our analysis of genomic sequence and in vitro data indicate that Parkin is a potential link between melanoma and Parkinson's disease. Our findings suggest new approaches for early diagnosis and treatment against both diseases.
- Melanoma,
- Parkinson's disease,
- Parkin,
- Mutation

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References(49)

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