Neuropathological mechanism common to lysosomal sphingolipid storage disease and Parkinson's disease
| Project/Area Number |
19K08288
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 52050:Embryonic medicine and pediatrics-related
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| Research Institution | Kawasaki Medical School |
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Principal Investigator |
Matsuda Junko 川崎医科大学, 医学部, 教授 (60363149)
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| Co-Investigator(Kenkyū-buntansha) |
渡邉 悦子 川崎医科大学, 医学部, 助教 (70378610)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| 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 / スフィンゴ糖脂質 / リソソーム病 |
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| Outline of Research at the Start |
サポシンはリソソームでのスフィンゴ脂質の分解に必須のタンパク質で、その異常は小児期発症の神経型リソソーム病を引き起こす。神経型リソソーム病の1つであるゴーシェ病の責任遺伝子グルコセレブロシダーゼ(GBA)の遺伝子変異はパーキンソン病の最大の遺伝的リスクである。本研究では、サポシンおよびその前駆体であるプロサポシンに着目し、神経型リソソーム病とパーキンソン病に共通する新たな神経病態メカニズムの解明に取り組む。
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| 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.
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| 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。
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Report
(4 results)
Research Products
(16 results)
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[Journal Article] Involvement of acid ceramidase in the degradation of bioactive N-acylethanolamines2021
Author(s)
Tsuboi Kazuhito、Tai Tatsuya、Yamashita Ryouhei、Ali Hanif、Watanabe Takashi、Uyama Toru、Okamoto Yoko、Kitakaze Keisuke、Takenouchi Yasuhiro、Go Shinji、Rahman Iffat Ara Sonia、Houchi Hitoshi、Tanaka Tamotsu、Okamoto Yasuo、Tokumura Akira、Matsuda Junko、Ueda Natsuo
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Journal Title
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
Volume: 1866
Issue: 9
Pages: 158972-158972
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Variants in saposin D domain of prosaposin gene linked to Parkinson’s disease2020
Author(s)
Oji Y, Hatano T, Ueno SI, Funayama M, Ishikawa KI, Okuzumi A, Noda S, Sato S, Satake W, Toda T, Li Y, Hino-Takai T, Kakuta S, Tsunemi T, Yoshino H, Nishioka K, Hattori T, Mizutani Y, Mutoh T, Yokochi F, et al.
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Journal Title
Brain
Volume: 143
Issue: 4
Pages: 1190-1205
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Novel neuroblastoma amplified sequence (NBAS) mutations in a Japanese boy with fever-triggered recurrent acute liver failure.2019
Author(s)
Ono S, Matsuda J, Watanabe E, Akaike H, Teranishi H, Miyata I, Otomo T, Sadahira Y, Mizuochi T, Kusano H, Kage M, Ueno H, Yoshida K, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Ogawa S, Hayashi Y, Kanegane H, Ouchi K.
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Journal Title
Hum Genome Var.
Volume: 7;6:2
Issue: 1
Pages: 1-9
DOI
Related Report
Peer Reviewed / Open Access
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