Physiological role of a presynaptic protein, NACP : Involvement in signal transduction systems

我们发现了阿尔茨海默病（AD）淀粉样蛋白的一个新成分，命名为NAC （AD淀粉样蛋白的非β成分），并克隆了编码NAC前体蛋白NACP的cDNA。特别值得注意的是，NACP的表达模式反映了典型AD病理的分布。斑块的数量不一定与认知障碍的严重程度相对应，而突触丧失的程度与认知障碍之间存在很强的相关性。NACP是一种突触前蛋白，因此，NACP的一些改变，包括突变，可能会影响突触功能，导致痴呆等症状。我们发现NACP不仅在突触区异常表达，而且在阿尔茨海默病脑营养不良的神经突中也异常表达。最近，在5个独立的家族性帕金森病（PD）家系中发现了两种分离疾病的NACP基因错义突变。我们通过免疫电镜发现，作为PD和DLB痴呆的神经病理学标志，路易小体的丝状成分中含有NACP的整个分子。据报道，重组NACP在体外形成类似路易小体的原纤维，并且这些突变加速了原纤维的形成。因此，NACP异常细丝在神经元、轴突和突触前区域内的积累可能会干扰神经元的功能，即神经传递，导致帕金森病和痴呆的症状，最终导致神经元细胞死亡。事实上，我们发现DLB海马穿孔通路的退行性末梢轴突含有nacp阳性的异常结构，而这些轴突的起源细胞仅含有少量路易小体，这表明由于轴突运输受阻而导致的“死后”变性过程。我们还发现，PD/DLB中不仅嗜银性胶质包涵体是NACP阳性，而且多系统萎缩的细胞质包涵体也含有整个NACP分子。这些发现提示NACP的改变可能主要参与几种不同神经退行性疾病的发病机制。少

We found a novel component of Alzheimer's disease (AD) amyloid, named NAC (non-Abeta component of AD amyloid) and cloned cDNA encoding NAC precursor protein, NACP.It should be noted in particular that expression pattern for NACP mirrors the distribution of typical AD pathology. The number of plaques does not necessarily correspond to the severity of cognitive impairment, while there is a strong correlation between the extent of synapse loss and the impairment. NACP is a presynaptic protein, and, therefore, some alterations of NACP including mutations could influence synaptic functions, leading to symptoms like dementia. We showed that NACP is aberrantly expressed not only in synaptic region, but also in dystrophic neurites in AD brain.Recently, two kinds of missense mutations in the NACP gene segregating the illness were found in five independent familial Parkinson's disease (PD) pedigrees. We showed that the filamentous components of Lewy bodies, aneuropathological hallmark of PD and … More of dementia with Lewy bodies (DLB) include entire molecule of NACP by immunoelectron microscopy. It was reported that recombinant NACP forms fibrils in vitro like Lewy bodies and the fibril formation is accelerated with those mutations. Thus, it is likely that the accumulation of abnormal filaments of NACP within neurons, axons, and presynaptic regions could interfere the function of neuron, i.e., neurotransmission, leading to Parkinsonisms and dementia as symptoms, and to neuronal cell death eventually. In fact, we showed that the degenerative teiminal axons of the perforant pathway in the hippocampus with DLB contain NACP-positive abnormal structures, while the origin cells of those axons contain only a few Lewy bodies, suggesting a 'dying back' degenerating process due to a blockage of axonal transport. We also revealed that not only argyrophilic glial inclusions in PD/DLB are NACP-positive, but also cytoplasmic inclusions of multiple system atrophy contain the whole NACP molecule. These findings suggest that the alteration of NACP may be involved primarily in the pathogenesis of several different neurodegenerative diseases. Less