FBXO7 Y52C Polymorphism as a Potential Protective Factor in Parkinson's Disease

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.

Structure and Function of Fbxo7/PARK15 in Parkinson's Disease

“…-Reduced capacity to recruit Parkin to mitochondria. [10,11,13,14,27,45,46] Other SNPs in FBXO7 have also recently been identified in relation to idiopathic PD; an allele encoding for p.Y52C is associated with decreased risk of disease in Chinese and Taiwanese patients [17], whereas a non-coding IVS-329C>T variant is moderately associated with increased risk [16]. Other GWAS studies have identified SNPs in FBXO7 as being relevant for measurable erythroid parameters, including one that causes a coding substitution (p.M115I) [18].…”

“…Other GWAS studies have identified SNPs in FBXO7 as being relevant for measurable erythroid parameters, including one that causes a coding substitution (p.M115I) [18]. However, no significant association between this SNP and PD has been found [17,19]. Mapping these pathogenic mutations and associated SNPs to different FBXO7 exons indicates that many of its functional protein domains may be affected to cause pathology; however, most of these alterations cluster in or around the N-terminal ubiquitin-like (Ubl) domain, or the C terminal F-box domain (FBD) and proline rich region (PRR) ( Figure 1A).…”

Mechanistic contributions of FBXO7 to Parkinson disease

“…The FBXO7 gene also displays various single-nucleotide polymorphisms (SNPs) and a recent study examined the cosegregation of PD and SNPs that generate the missense mutations Y52C and M115I. The results revealed significantly fewer individuals with PD that carry the G allele of the Y52C SNP (Chen et al 2014), suggesting a protective genotype. While this is an intriguing finding, the minor allelic frequency of the G allele in the control group is very low, which requires further validation with larger cohorts.…”

Loss of FBXO7 results in a Parkinson's‐like dopaminergic degeneration via an RPL23–MDM2–TP53 pathway

“…In 2008, a point mutation in FBXO7 was linked to a familial form of PD , presenting an early‐onset Parkinsonism with pyramidal signs. Subsequently additional mutations have been found in early‐onset cases and in patients with sporadic PD . PARK15 PD patients are levodopa‐responsive, but rapidly develop side effects, such as dyskinesia .…”