| Project/Area Number |
15KK0309
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| Research Category |
Fund for the Promotion of Joint International Research (Fostering Joint International Research)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Pathological medical chemistry
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| Research Institution | The University of Tokushima |
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Principal Investigator |
TSUJI Daisuke 徳島大学, 大学院医歯薬学研究部(薬学域), 助教 (00423400)
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| Research Collaborator |
Ballabio Andrea Telethon Institute of Genetics and Medicine, 所長
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| Project Period (FY) |
2016 – 2018
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥14,300,000 (Direct Cost: ¥11,000,000、Indirect Cost: ¥3,300,000)
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| Keywords | リソソーム / オートファジー / リソソーム病 / ガングリオシド / TFEB / 糖脂質 / 脳神経疾患 |
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| Outline of Final Research Achievements |
Transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and autophagy. Under lysosomal stress conditions, TFEB translocates from the cytoplasm to the nucleus, resulting in the activation of its target genes. However, the distribution of endogenous TFEB in lysosomal storage disorders is uncharacterized. Here we show that endogenous TFEB in LSD model mice with neurological symptoms (such as multiple sulfatase deficiency, Sandhoff disease and mucopolysaccharidosis IIIA is induced and activated by neuro-inflammation . In addition, the response of TFEB in LPS induced neuro-inflammation model is the same as LSD model. Thus, neuro-inflammation in the brain causes up-regulation and activation of endogenous TFEB. Furthermore, neuronal apoptosis and glial activation were observed in DKO (Hexb and Tfeb KO) brains. In conclusion, Tfeb is important in neuronal survival with lysosomal disease via regulation of lysosomal biogenesis and autophagy.
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| Academic Significance and Societal Importance of the Research Achievements |
リソソーム病は、リソソームに存在する加水分解酵素の遺伝的欠損により発症する。生体内基質のリソソームへの過剰な蓄積により様々な症状を呈する先天性代謝異常症であり、わが国において難病指定されている。本研究成果は、治療法が存在しない中枢神経症状を呈するリソソーム病において、リソソーム生合成を司る転写因子TFEBが、オートファジー異常を改善することで神経保護的に働いていることを明らかにした。これらの成果により、新たな治療法が期待される。
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