Mechanisms of neurodegeneration with NACP/α-synuclein, a causal gene of Parkinson's disease

NACP/α-突触核蛋白（帕金森病的致病基因）引起的神经变性机制

基本信息

批准号：
11680774
负责人：
UEDA Kenji
金额：
$ 1.6万
依托单位：
Tokyo Metropolitan Organization for Medical Research
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11680774/
关键词：
NACP synuclein Alzheimer Parkinson MSA Lewy bodies Alzheimaer

项目摘要

We have found a novel component of Aizheimer's disease (AD) amyloid, named NAG (non-Abeta component of AD 'amyloid) and cloned the cDNA encoding NAG precursor protein, NACP. NACP is now known as human aipha-synuclein. We have shown that aipha-synuclein is aberrantly expressed not only in synaptic regions, but also In dystrophic neurites in AD brains. Recently, missense mutations In the alpha-synuclein gene were found in familial Parkinson's disease (PD) pedigrees In an autosomal dominant fashion and were shown to segregate with the illness. We have shown that entire molecule of aipha-synuclein constitutes filamentous components of Lewy bodies, a neuropathologlcal hallmark of PD and of dementia with Lewy bodies (DLB), and cytopiasmic inclusions of multiple system atrophy (MSA). It has been shown that recombinant aipha-synuclein forms fibrils in vitro like Lewy bodies and that the fibril formation Is accelerated with those mutations.Thus, aipha-synuclein is a common pathogenic molecule In these degenerative diseases, and it seems that the accumulation of abnormal structures of aipha-synuclein within neurons, axons, dendrites, and presynaptic regions interfere the function of neuron, I.e., neurotransmlssion, leading to Parkinsonism and dementia as symptoms, and eventually to neuronal cell death. We have shown that the NAG region of aipha-synuclein, which is shown to be important for fibrillogenesis, is hard to digest by some protelnases. We also have revealed that tubulin is an alpha-synuclein-binding protein and that tubulin seeds aipha-synuclein fibril formation. We have cloned the gene for human aipha-synuclein and revealed the genomic structure of this gene, and found that there are polymorphisms in the promoter region and in an exon of aipha-synuclein gene.

我们发现了艾兹海默病（AD）淀粉样蛋白的一种新成分，命名为NAG（AD淀粉样蛋白的非Abeta成分），并克隆了编码NAG前体蛋白NACP的cDNA。 NACP 现在被称为人类 aipha-突触核蛋白。我们已经证明，aipha-突触核蛋白不仅在突触区域异常表达，而且在 AD 大脑的营养不良神经突中也异常表达。最近，在家族性帕金森病 (PD) 家系中发现了 α-突触核蛋白基因中的错义突变，该突变以常染色体显性方式出现，并被证明与该疾病分离。我们已经证明，α-突触核蛋白的整个分子构成了路易体的丝状成分，路易体是帕金森病和路易体痴呆（DLB）的神经病理学标志，以及多系统萎缩（MSA）的细胞质包涵体。已经表明，重组aipha-synuclein在体外像路易体一样形成原纤维，并且这些突变加速了原纤维的形成。因此，aipha-synuclein是这些退行性疾病中常见的致病分子，并且似乎异常积累神经元、轴突、树突和突触前区域内的 aipha-突触核蛋白结构干扰神经元的功能，即神经传递、导致帕金森症和痴呆症的症状，并最终导致神经元细胞死亡。我们已经证明，aipha-突触核蛋白的 NAG 区域对于原纤维形成很重要，但很难被一些蛋白酶消化。我们还揭示了微管蛋白是一种α-突触核蛋白结合蛋白，并且微管蛋白促进α-突触核蛋白原纤维的形成。我们克隆了人aipha-synuclein基因，并揭示了该基因的基因组结构，发现aipha-synuclein基因的启动子区和外显子存在多态性。