Neuropathological mechanism common to lysosomal sphingolipid storage disease and Parkinson's disease

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08288
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Kawasaki Medical School
• Principal Investigator: Matsuda Junko 川崎医科大学, 医学部, 教授 (60363149)
• Co-Investigator(Kenkyū-buntansha): 渡邉 悦子 川崎医科大学, 医学部, 助教 (70378610)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: リソソーム蓄積病 / スフィンゴリピドーシス / スフィンゴ脂質 / プロサポシン / サポシン / パーキンソン病

Outline of Final Research Achievements

Prosaposin (PSAP) is a precursor protein of four hydrophobic glycoproteins, called saposins (SAPs)-A, B, C, D, which are essential along with hydrolases for the degradation of sphingolipids in lysosomes. Heterozygous gene mutations in the SAP-D region of PSAP gene have been reported in patients with autosomal dominantly inherited familial Parkinson's disease. We performed an comparative proteomic analysis of the substantia nigra of Sap-D mutant mice, and found that PSAP was oligomerized and accumulated significantly in the substantia nigra of Sap-D mutant mice. Immunohistochemically, the PSAP specific antibody immuno-positive inclusion bodies were observed in the dopaminergic neurons of substantia nigra. Oligomerized and accumulated PSAP may have neurotoxicity for the dopaminergic neurons in the substantia nigra.

Free Research Field

小児科学、先天代謝異常症、脂質生化学

Academic Significance and Societal Importance of the Research Achievements

PSAPの蓄積は、神経型リソソーム病である神経セロイドリポフスチン症や、前頭側頭葉変性症でも指摘されており、神経細胞内にオリゴマー化して異常蓄積したPSAPが、神経細胞毒性を持ち、神経変性疾患を惹起する可能性がある。本研究の成果は、Rare diseaseである神経型リソソーム病と、Common diseaseであるパーキンソン病やアルツハイマー病に共通する新たな神経病態仮説－プロサポシノパチー（prosaposinopathy）－の提唱につながるものである。