FBXO7 Y52C polymorphism as a potential protective factor in Parkinson's disease

Chiung Mei Chen, I. G. Chen, Yi Cheng Huang, Hsueh Fen Juan, Ying Lin Chen, Yi Chun Chen, Chih Hsin Lin, Li Ching Lee, Chi Mei Lee, Guey Jen Lee-Chen, Yun Ju Lai, Yih Ru Wu

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article numbere101392
JournalPLoS One
Volume9
Issue number7
DOIs
Publication statusPublished - 2014 Jul 16

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F-Box Proteins
F-box proteins
Parkinson disease
Polymorphism
Parkinson Disease
Genes
genetic polymorphism
TNF Receptor-Associated Factor 2
Proteins
genes
receptors
Cells
Gene Frequency
gene frequency
cells
SKP Cullin F-Box Protein Ligases
Protective Factors
ubiquitin-protein ligase
Ubiquitin-Protein Ligases
Ubiquitination

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Chen, C. M., Chen, I. G., Huang, Y. C., Juan, H. F., Chen, Y. L., Chen, Y. C., ... Wu, Y. R. (2014). FBXO7 Y52C polymorphism as a potential protective factor in Parkinson's disease. PLoS One, 9(7), [e101392]. https://doi.org/10.1371/journal.pone.0101392

FBXO7 Y52C polymorphism as a potential protective factor in Parkinson's disease. / Chen, Chiung Mei; Chen, I. G.; Huang, Yi Cheng; Juan, Hsueh Fen; Chen, Ying Lin; Chen, Yi Chun; Lin, Chih Hsin; Lee, Li Ching; Lee, Chi Mei; Lee-Chen, Guey Jen; Lai, Yun Ju; Wu, Yih Ru.

In: PLoS One, Vol. 9, No. 7, e101392, 16.07.2014.

Research output: Contribution to journalArticle

Chen, CM, Chen, IG, Huang, YC, Juan, HF, Chen, YL, Chen, YC, Lin, CH, Lee, LC, Lee, CM, Lee-Chen, GJ, Lai, YJ & Wu, YR 2014, 'FBXO7 Y52C polymorphism as a potential protective factor in Parkinson's disease', PLoS One, vol. 9, no. 7, e101392. https://doi.org/10.1371/journal.pone.0101392
Chen CM, Chen IG, Huang YC, Juan HF, Chen YL, Chen YC et al. FBXO7 Y52C polymorphism as a potential protective factor in Parkinson's disease. PLoS One. 2014 Jul 16;9(7). e101392. https://doi.org/10.1371/journal.pone.0101392
Chen, Chiung Mei ; Chen, I. G. ; Huang, Yi Cheng ; Juan, Hsueh Fen ; Chen, Ying Lin ; Chen, Yi Chun ; Lin, Chih Hsin ; Lee, Li Ching ; Lee, Chi Mei ; Lee-Chen, Guey Jen ; Lai, Yun Ju ; Wu, Yih Ru. / FBXO7 Y52C polymorphism as a potential protective factor in Parkinson's disease. In: PLoS One. 2014 ; Vol. 9, No. 7.
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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.",
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