Association between conformational mutations in neuroserpin and onset and severity of dementia
Association between conformational mutations in neuroserpin and onset and severity of dementia
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DOI：
10.1016/s0140-6736(02)09293-0
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发表时间：
2002-06-29
期刊：
影响因子：
168.9
通讯作者：
Holohan, PD
中科院分区：
文献类型：
--
作者：
Davis, RL;Shrimpton, AE;Holohan, PD
背景特定蛋白质的聚集是家族性痴呆的共同特征，但神经元包涵体的形成是否是该疾病的致病因素或偶然因素尚不清楚。为了澄清这个问题，我们调查了5个具有典型神经丝氨酸蛋白酶包涵体但具有不同神经学表现的家系。方法对5个患有神经退行性疾病和典型神经元包涵体的家系有活检或尸检材料可供进一步检查。免疫染色证实，内含物是由神经丝氨酸蛋白酶抑制剂聚集体形成的，并且通过对血液样本或组织学标本提取的 DNA 中的神经丝氨酸蛋白酶抑制剂基因 (SERPINI1) 进行测序，鉴定了神经丝氨酸蛋白酶抑制剂的相关突变。分子建模技术用于预测基因突变对三维蛋白质结构的影响。对脑切片进行染色并绘制神经丝氨酸蛋白酶抑制剂内含物的拓扑分布。结果每个家族对于影响神经丝氨酸蛋白酶抑制剂构象稳定性的氨基酸取代都是杂合的。正如分子模型所预测的，这些突变中破坏性最小的 (S49P) 会导致 45 岁后痴呆，并且仅在少数神经元中存在神经丝氨酸蛋白酶抑制剂。相比之下，最严重的破坏性突变 (G392E) 在 13 岁时导致进行性肌阵挛癫痫，几乎所有神经元中都存在许多包涵体。解释这些发现提供的证据表明，包涵体形成本身就是神经退行性变的充分原因，并且该疾病的发作和严重程度与神经元蛋白质聚集的速率和程度有关。
Background The aggregation of specific proteins is a common feature of the familial dementias, but whether the formation of neuronal inclusion bodies is a causative or incidental factor in the disease is not known. To clarify this issue, we investigated five families with typical neuroserpin inclusion bodies but with various neurological manifestations.Methods Five families with neurodegenerative disease and typical neuronal inclusions had biopsy or autopsy material available for further examination. Immunostaining confirmed that the inclusions were formed of neuroserpin aggregates, and the responsible mutations in neuroserpin were identified by sequencing of the neuroserpin gene (SERPINI1) in DNA from blood samples or from extraction of histology specimens. Molecular modelling techniques were used to predict the effect of the gene mutations on three-dimensional protein structure. Brain sections were stained and the topographic distribution of the neuroserpin inclusions plotted.Findings Each of the families was heterozygous for an aminoacid substitution that affected the conformational stability of neuroserpin. The least disruptive of these mutations (S49P), as predicted by molecular modelling, resulted in dementia after age 45 years, and presence of neuroserpin inclusions in only a few neurons. By contrast, the most severely disruptive mutation (G392E) resulted, at age 13 years, in progressive myoclonus epilepsy, with many inclusions present in almost all neurons.Interpretation The findings provide evidence that inclusion-body formation is in itself a sufficient cause of neurodegeneration, and that the onset and severity of the disease is associated with the rate and magnitude of neuronal protein aggregation.