TY - JOUR
T1 - Parkin Somatic Mutations Link Melanoma and Parkinson's Disease
AU - Levin, Lotan
AU - Srour, Shani
AU - Gartner, Jared
AU - Kapitansky, Oxana
AU - Qutob, Nouar
AU - Dror, Shani
AU - Golan, Tamar
AU - Dayan, Roy
AU - Brener, Ronen
AU - Ziv, Tamar
AU - Khaled, Mehdi
AU - Schueler-Furman, Ora
AU - Samuels, Yardena
AU - Levy, Carmit
N1 - Publisher Copyright:
© 2016
PY - 2016/6/20
Y1 - 2016/6/20
N2 - 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.
AB - 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.
KW - Melanoma
KW - Mutation
KW - Parkin
KW - Parkinson's disease
UR - http://www.scopus.com/inward/record.url?scp=84978114962&partnerID=8YFLogxK
U2 - 10.1016/j.jgg.2016.05.005
DO - 10.1016/j.jgg.2016.05.005
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AN - SCOPUS:84978114962
SN - 1673-8527
VL - 43
SP - 369
EP - 379
JO - Journal of Genetics and Genomics
JF - Journal of Genetics and Genomics
IS - 6
ER -