Title "Molecular Pathogenesis of Parkinson's Disease"

标题“帕金森病的分子发病机制”

• 批准号: 12210006
• 负责人: IWATSUBO Takeshi
• 金额: $ 69.7万
• 依托单位: University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12210006/
• 关键词: Parkinson's disease; a-synuclein; Lewy body; phosphorylation; ubiquitination; neuronal death; 神経科学; 脳神経疾患; 老化; αシヌクレイン; Lewy小体痴呆症; 神経変性疾患; Lewy小体型痴呆症; α-Synuclein

To elucidate the molecular pathogenesis of sporadic Parkinson's disease (PD) and dementia with Lewy bodies (DLB), we examined the alterations, especially posttranslational modifications, of α-synuclein (aS) that gets deposited in affected neurons of PD and DLB as fibrillary aggregates represented by Lewy bodies (LB). We analyzed aS purified from insoluble fractions of DLB cortices and demonstrated by mass spectrometry that Ser129 of deposited aS is phosphorylated. Phosphorylated Ser129-specific antibody revealed extensive deposition of aS as intracellular inclusions like LBs, as well as thread-or dot-like deposits in degenerating neurites. A fraction of phosphorylated aS was mono-ubiquitinated at the N- terminal Lys residues. Proteinase K digestion of aS filaments showed that the mid-portion of aS comprises the protease-resistant core structure. Transgenic Drosophila expressing aS in neurons exhibited phosphorylation of aS in a subset of neurons. Co-expression of aS and synphilin-1 in mammalian cultured cells showed that phosphorylation of aS at Ser129 contributes to aggregate formation and cell death. Based on these results, we seek to develop therapeutic strategies to prevent neuronal death in PD or DLB, by inhibiting noxious post-translational modification of aS and other pathogenic proteins.

为了阐明散发性帕金森病（PD）和路易体痴呆（DLB）的分子发病机制，我们研究了α-突触核蛋白（aS）的改变，特别是翻译后修饰，它们以路易体（LB）为代表的聚集体沉积在PD和DLB的受累神经元中。我们分析了从DLB皮质的不溶性组分纯化的aS，并通过质谱证明沉积的aS的Ser 129被磷酸化。磷酸化Ser 129-特异性抗体显示AS广泛沉积为细胞内包涵体，如LB，以及线或点样沉积在退化的神经突。一部分磷酸化的aS在N-末端Lys残基处被单泛素化。蛋白酶K消化的aS丝表明，中间部分的aS包括抗蛋白酶的核心结构。在神经元中表达aS的转基因果蝇在一个神经元子集中表现出aS的磷酸化。在哺乳动物培养细胞中的aS和synphilin-1的共表达表明，在Ser 129的aS的磷酸化有助于聚集体的形成和细胞死亡。基于这些结果，我们寻求开发治疗策略，以防止PD或DLB中的神经元死亡，通过抑制有害的翻译后修饰的aS和其他致病蛋白。

项目成果

Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an α-synuclein rat model of Parkinson's disease

• DOI: 10.1073/pnas.0405313101
• 发表时间: 2004-12-14
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Lo Bianco, C;Schneider, BL;Aebischer, P
• 通讯作者: Aebischer, P

Piao Y-S: "Co-localization of α-synuclein and phosphorylated tau in neuronal and glial cytoplasmic inclusions in a patient with multiple system atrophy of long duration"Acta Neuropathol. 101. 285-293 (2001)

Piao Y-S：“长期多系统萎缩患者的神经元和胶质细胞质内含物中 α-突触核蛋白和磷酸化 tau 蛋白的共定位”《神经病理学报》101. 285-293 (2001)。

Iwatsubo T: "Amyloid deposits and plaque formation Neurodegenerative Dementias. Edited by Christopher M. Clark and John Q. Trojanowski."McGraw-Hill. 10 (2000)

Iwatsubo T：“淀粉样蛋白沉积和斑块形成神经退行性痴呆。由 Christopher M. Clark 和 John Q. Trojanowski 编辑。”McGraw-Hill。

Wakabayashi K,Fukushima T,Koide R,Horikawa Y,Hasegawa M,Watanabe Y,Noda T,Eguchi I,Morita T,Yoshimoto M,Iwatsubo T,Takahashi H: "Juvenile-onset generalized neuroaxonal dystrophy (Hallervorden-Spatz disese) with diffuse neurofibrillary and Lewy body pathol

Wakabayashi K、Fukushima T、Koide R、Horikawa Y、Hasekawa M、Watanabe Y、Noda T、Eguchi I、Morita T、Yoshimoto M、Iwatsubo T、Takahashi H：“青少年发病的广泛性神经轴索营养不良症（Hallervorden-Spatz 病）

Miake H: "Biochemical characterization of the core structure of α-synuclein filaments"J Biol Chem. 277. 19213-19219 (2002)

Miake H：“α-突触核蛋白丝核心结构的生化表征”J Biol Chem. 277. 19213-19219 (2002)