Disease modeling and development of therapies for Stargardt disease with PRPH2 mutations

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K16936
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56060:Ophthalmology-related
• Research Institution: Juntendo University
• Principal Investigator: Arai Eisuke 順天堂大学, 医学部, 非常勤助教 (60568210)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Keywords: PRPH2 / A2E / Stargardt disease / ABCA4 / RDH12 / ER stress

Outline of Final Research Achievements

We compared Prph2Rd2/wt mice, Prph2Rd2/Rd2 mice, Abac4-/- mice and WT mice at 3 weeks, 4 months and 8 months of age.
ONL was significantly thinner in Prph2Rd2/wt and Prph2Rd2/Rd2 mice than WT, suggesting that Prph2Rd2/wt and Prph2Rd2/Rd2 mice display retinal degeneration during aging. Moreover, Prph2Rd2/wt mice showed moderate degeneration compared to Prph2Rd2/Rd2 mice. We found accumulations of A2E and Lipofuscin which cause retinal degeneartion in Prph2Rd2/wt mice as well as Abac4-/- mice.
Expressions of Abca4 and Rdh12 in Prph2Rd2/wt mice were significantly reduced compared to WT. These results provide evidence that reduced Abca4 and Rdh12 expressions might contribute to accumulations of A2E and Lipofuscin in Prph2Rd2/wt mice. Expressions of ER stress markers significantly increased in Prph2Rd2/wt mice, suggesting that reduced RDH12 expressions in Prph2Rd2/wt mice might correlate with unfolded protein response.

Free Research Field

網膜変性疾患

Academic Significance and Societal Importance of the Research Achievements

Stargardt病は、構造タンパク質であるPRPH2の変異によっても発症する事がわかっているが発症機序は不明である。モデルマウスによってPRPH2変異によって発症するStargardt病もABCA4の変異のStargardt病と同様にA2Eやリポフスチンの蓄積していた。また、ABCA4とRDH12の機能異常がA2Eやリポフスチンの蓄積させる原因となっており、RDH12の機能異常には小胞体ストレス応答が関与している可能性が示唆された。
本研究によってPRPH2変異によるStargardt病の病態解明と治療法の開発につながり、学術的かつ社会的に意義が高いものであると考えられる。