Parkin Somatic Mutations Link Melanoma and Parkinson's Disease.
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.
Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Lotan
L
Levin
Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Shani
S
Srour
Surgery Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Jared
J
Gartner
Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Oxana
O
Kapitansky
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
Nouar
N
Qutob
Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Shani
S
Dror
Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Tamar
T
Golan
Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Roy
R
Dayan
Oncology Institute, Edith Wolfson Medical Center, Holon 5822012, Israel.
Ronen
R
Brener
Technion Smoler Proteomics Center, Faculty of Biology, Technion - Israel Institute of Technology, Haifa 32000, Israel.
Tamar
T
Ziv
Institut Gustave Roussy, INSERM U753, Villejuif 94805, France.
Mehdi
M
Khaled
Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University, Jerusalem 91120, Israel.
Ora
O
Schueler-Furman
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
Yardena
Y
Samuels
Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: carmitlevy@post.tau.ac.il.
Carmit
C
Levy
D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D008958:Models, Molecular; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology; D000072417:Protein Domains; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D005819:Genetic Markers; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein
Melanoma; Mutation; Parkin; Parkinson's disease