Detection of genetic modifiers in PRKN

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K14966
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Juntendo University
• Principal Investigator: Ogaki Kotaro 順天堂大学, 医学部, 准教授 (20459035)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: パーキンソン病 / 遺伝子 / 疾患修飾遺伝子 / parkin / 神経科学 / 次世代シーケンサー

Outline of Final Research Achievements

In this study, we investigated whether disease modifier genes are associated with the onset of PD with heterozygous PRKN mutations. We performed targeted sequencing and sequenced the genes which are previously known as PD genes, functionally associated with PRKN protein, and associated with lysosomal storage disease (total 79 genes). We enrolled 3 groups (total 285 subjects): (i) PD with heterozygous PRKN mutations (n=50), (ii) PD with homozygous mutations whose parents are not PD (n=105), (iii) healthy controls (n=130).The frequency of variant A in Gene X was significantly increased in heterozygous PRKN group compared to Healthy control group. (19% vs 10%, P=0.035, OR 2.02, 95%CI 1.00-4.00). We found a potential genetic modifier of PRKN, Variant A in Gene X as a risk factor. Gene A was previously reported to protect against neuronal death in cellular Parkinson‘s disease models by maintaining levels of PRKN. Further studies are warranted to confirm the genetic modifiers of PRKN.

Free Research Field

神経内科

Academic Significance and Societal Importance of the Research Achievements

当研究室より報告されたparkin遺伝子変異は、若年性PD患者の原因遺伝子としてその頻度は本邦・世界で最多であり、parkin家系において、発症予防法・進行予防法の開発は喫緊の課題である。Gene Aはparkinの発現量を調整することで、PDの細胞モデルで細胞死に対し保護的に働くことが知られている。現在、細胞実験系を用いて gene Xのvariant Aがparkinの発現に与える影響を確認中である。本研究は、parkin 1アレル変異患者の発症予防法・進行予防法開発につながる可能性があり、その社会的意義は大きいと考える。