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 P...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 in3.6% 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-E28 K 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.展开更多
基金support from I-CORE (grant number 41/11)the Israel Cancer Association (ICA) (grant number 20150101)+2 种基金Israel Cancer Research Fund (ICRF) (grant number RCBA-11706)Fritz Thyssen Stiftung (grant number AZ.10.12.1.188)Marie Curie Career Integration Grants (CIG) (grant number 293594)
文摘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 in3.6% 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-E28 K 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.
