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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)369-379
Number of pages11
JournalJournal of Genetics and Genomics
Volume43
Issue number6
DOIs
StatePublished - 20 Jun 2016

Funding

FundersFunder number
Fingerhot Carol and Lionara Fund
Israel Cancer Research FundRCBA-11-706
Marie Curie293594
Fritz Thyssen Stiftung10.12.1.188
Israel Cancer Association20150101
Israeli Centers for Research Excellence41/11

    Keywords

    • Melanoma
    • Mutation
    • Parkin
    • Parkinson's disease

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