Parkin Somatic Mutations Link Melanoma and Parkinson's Disease.
J Genet Genomics
; 43(6): 369-79, 2016 06 20.
Article
em En
| MEDLINE
| ID: mdl-27297116
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doença de Parkinson
/
Ubiquitina-Proteína Ligases
/
Melanoma
/
Mutação
Tipo de estudo:
Prognostic_studies
/
Screening_studies
Limite:
Humans
Idioma:
En
Revista:
J Genet Genomics
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Israel