FBXO7 Y52C polymorphism as a potential protective factor in Parkinson's disease
Journal
PLoS ONE
Journal Volume
9
Journal Issue
7
Pages
e101392
Date Issued
2014
Author(s)
Abstract
Mutations in the F-box only protein 7 gene (FBXO7), the substrate-specifying subunit of SCF E3 ubiquitin ligase complex, cause Parkinson's disease (PD)-15 (PARK15). To identify new variants, we sequenced FBXO7 cDNA in 80 Taiwanese early onset PD patients (age at onset ?50) and only two known variants, Y52C (c.155A>G) and M115I (c.345G>A), were found. To assess the association of Y52C and M115I with the risk of PD, we conducted a case-control study in a cohort of PD and ethnically matched controls. There was a nominal difference in the Y52C G allele frequency between PD and controls (p = 0.045). After combining data from China [1], significant difference in the Y52C G allele frequency between PD and controls (p = 0.012) and significant association of G allele with decreased PD risk (p = 0.017) can be demonstrated. Upon expressing EGFP-tagged Cys52 FBXO7 in cells, a significantly reduced rate of FBXO7 protein decay was observed when compared with cells expressing Tyr52 FBXO7. In silico modeling of Cys52 exhibited a more stable feature than Tyr52. In cells expressing Cys52 FBXO7, the level of TNF receptor-associated factor 2 (TRAF2) was significantly reduced. Moreover, Cys52 FBXO7 showed stronger interaction with TRAF2 and promoted TRAF2 ubiquitination, which may be responsible for the reduced TRAF2 expression in Cys52 cells. After induced differentiation, SH-SY5Y cells expressing Cys52 FBXO7 displayed increased neuronal outgrowth. We therefore hypothesize that Cys52 variant of FBXO7 may contribute to reduced PD susceptibility in Chinese. ? 2014 Chen et al.
SDGs
Other Subjects
complementary DNA; enhanced green fluorescent protein; tumor necrosis factor receptor associated factor 2; 1 methyl 4 phenylpyridinium; F box protein; FBXO7 protein, human; tumor necrosis factor receptor associated factor 2; adult; allele; article; case control study; cell differentiation; China; cohort analysis; computer model; controlled study; disease predisposition; ethnic group; FBXO7 gene; female; gene; gene expression; gene frequency; gene mutation; gene overexpression; gene repression; gene sequence; genetic association; genetic stability; genetic variability; human; human cell; major clinical study; male; nerve fiber growth; nucleotide sequence; Parkinson disease; protein expression; protein protein interaction; sequence homology; single nucleotide polymorphism; Taiwan; Taiwanese; ubiquitination; amino acid sequence; animal; cell survival; chemical structure; chemistry; drug effects; gene expression regulation; genetic predisposition; genetics; metabolism; middle aged; molecular genetics; mutation; Parkinson disease; pathology; protection; protein secondary structure; protein stability; toxicity; tumor cell line; young adult; 1-Methyl-4-phenylpyridinium; Adult; Amino Acid Sequence; Animals; Case-Control Studies; Cell Line, Tumor; Cell Survival; F-Box Proteins; Female; Gene Expression Regulation; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Models, Molecular; Molecular Sequence Data; Mutation; Parkinson Disease; Polymorphism, Single Nucleotide; Protective Factors; Protein Stability; Protein Structure, Secondary; Sequence Homology, Amino Acid; TNF Receptor-Associated Factor 2; Ubiquitination; Young Adult
Publisher
PLoS
Type
journal article