Proteasome regulates dopaminergic neuronel degeneration and Lewy body formation

蛋白酶体调节多巴胺能神经元变性和路易体形成

• 批准号: 14570591
• 负责人: SAWADA Hideyuki
• 金额: $ 2.56万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570591/
• 关键词: Parkinson's disease; α-synuclein; MPP^+; rotenone; proteasome; Lewy body; dopamine; ミトコンドリア; ニューロン死; ドーパミンニューロン; MPTP; MPP+

Parkinson's disease is characterized by dopaminergic neuronal death and the presence of Lewy bodies. α-Synuclein is a major component of Lewy bodies, but the process of its accumulation and its relationship to dopaminergic neuronal death have not been resolved. Although the pathogenesis has not been clarified, mitochondrial complex I is suppressed and caspase-3 is activated in the affected midbrain. In this research project, we demonstrated that a combination of 1-methyl-4-phenylpyridinium ion (MPP^+) or rotenone and proteasome inhibition caused the appearance of α-synuclein positive inclusion bodies. Unexpectedly, however, proteasome inhibition blocked MPP^+-or rotenone-induced dopaminergic neuronal death. MPP^+ elevated the activity of 26S proteasome, dephosphorylated mitogen activating kinase (MAPK) and activated caspase-3. Proteasome inhibition reversed the MAPK dephosphorylation and blocked caspase-3 activation; the neuroprotection was blocked by a p-42 and p-44 MAPK kinase inhibitor. Thus the proteasome plays an important role in both inclusion body formation and dopaminergic neuronal death but these processes form opposite sides on the proteasome regulation in this model.

帕金森病的特征在于多巴胺能神经元死亡和路易体的存在。α-突触核蛋白是路易体的主要成分，但其积累过程及其与多巴胺能神经元死亡的关系尚未得到解决。虽然发病机制尚未阐明，线粒体复合物I被抑制，caspase-3被激活，在受影响的中脑。在本研究项目中，我们证明了1-甲基-4-苯基吡啶离子（MPP^+）或鱼藤酮与蛋白酶体抑制剂的组合导致α-突触核蛋白阳性包涵体的出现。然而，出乎意料的是，蛋白酶体抑制剂阻断了MPP^+或鱼藤酮诱导的多巴胺能神经元死亡。MPP^+使26 S蛋白酶体、去磷酸化丝裂原活化激酶（MAPK）和活化半胱天冬酶-3的活性升高。蛋白酶体抑制逆转MAPK去磷酸化，阻断caspase-3激活;神经保护作用被p-42和p-44 MAPK激酶抑制剂阻断。因此，蛋白酶体在包涵体形成和多巴胺能神经元死亡中起重要作用，但这些过程在该模型中形成蛋白酶体调节的相反侧。

项目成果

Shimohama S: "Disease model : Parkinson's disease"Trends in Molecular Medicine. 9・8. 360-365 (2003)

Shimohama S：“疾病模型：帕金森病”分子医学趋势 9・8（2003）。

Sawada H. et al.: "Proteasome mediates dopaminergic neuronal degeneration, and its inhibition causes α-Synuclein inclusions"J.Biol.Chem. 279. 10710-10719 (2004)

Sawada H. 等人：“蛋白酶体介导多巴胺能神经元变性，其抑制导致 α-突触核蛋白包涵体”J.Biol.Chem. 279. 10710-10719 (2004)

Kohno R. et al.: "BDNF is induced by wild-type α-synuclein but not by the two mutants, A30P or A53T, in glioma cell line."Biochem.Biophys.Res.Commun.. 318. 113-118 (2004)

Kohno R. 等人：“在神经胶质瘤细胞系中，BDNF 是由野生型 α-突触核蛋白诱导的，但不是由两种突变体 A30P 或 A53T 诱导的。”Biochem.Biophys.Res.Commun.. 318. 113-118 ( 2004）

Sawada H, Ibi M, KiharaT, Honda K, Nakanishi M, Sakka N, Akaike A, Shimohama S.: "Estradiol protects dopaminergic neurons in a MPP^+ Parkinson's disease model."Neuropharm acology. 42. 1056-1064 (2002)

Sawada H、Ibi M、KiharaT、Honda K、Nakanishi M、Sakka N、Akaike A、Shimohama S.：“雌二醇保护 MPP^ 帕金森病模型中的多巴胺能神经元。”Neuropharm acology。

Sakka N et al.: "Dopamine is involved in selectivity of dopaminergic neuronal death by roteuone."Neuroreport. 14. 2425-2428 (2003)

Sakka N 等人：“多巴胺参与 roteuone 引起的多巴胺能神经元死亡的选择性。”Neuroreport。