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

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Aβ成分)，并克隆了编码NAG前体蛋白NACP的基因。NACP现在被称为人类α-突触核蛋白。我们已经证明，α-突触核蛋白不仅在突触区域异常表达，而且在AD脑中营养不良的神经元中也有异常表达。最近，在家族性帕金森病(PD)家系中发现了α-突触核蛋白基因的错义突变，这种突变以常染色体显性方式存在，并被证明与疾病分离。我们已经证明，α-突触核蛋白的整个分子组成了路易小体的丝状成分，是帕金森病和路易体痴呆(DLB)的神经病理标志，以及多系统萎缩的细胞分裂包涵体(MSA)。已有研究表明，重组α-突触核蛋白在体外可形成类似路易小体的纤维，并随着这些突变而加速纤维的形成。因此，α-突触核蛋白是这些退行性疾病的常见致病分子，似乎是α-突触核蛋白在神经元、轴突、树突和突触前区域的异常结构积聚干扰了神经元的功能，即神经传递，导致帕金森病和痴呆作为症状，最终导致神经细胞死亡。我们已经证明，α-突触核蛋白的NAG区域被证明是纤维形成的重要部分，很难被一些蛋白端酶消化。我们还揭示了微管蛋白是一种α-突触核蛋白结合蛋白，并且微管蛋白种子α-突触核蛋白原纤维的形成。我们克隆了人α-突触核蛋白基因，并揭示了该基因的基因组结构，发现α-突触核蛋白基因的启动子区域和一个外显子存在多态性。

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.