Analysis of the P/Q-type calcium channel in autopsied patients with paraneoplastic cerebellar degeneration (PCD) and Lambert-Eaton myasthenic syndrome (LEMS)

副肿瘤性小脑变性（PCD）和兰伯特-伊顿肌无力综合征（LEMS）尸检患者 P/Q 型钙通道分析

• 批准号: 13670654
• 负责人: MOTOMURA Masakatsu
• 金额: $ 2.24万
• 依托单位: Nagasaki University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670654/
• 关键词: Lambert-Eaton myasthenic syndrome (LEMS); paraneoplastic cerebellar degeneration (PCD); P; Q-type voltage-gated calcium channel (P; Q-type VGCC); autoantibodies; cerebellum; autoradiography; molecular laye; Purkinje cell; Lambert-Eaton筋無力症侯群; 電

The aim of this study was to clarify whether autoimmunity against P/Q-type voltage-gated calcium channels (VGCC) in the cerebellum was associated with the pathogenesis of paraneoplastic cerebellar degeneration (PCD) with Lambert-Eaton myasthenic syndrome (LEMS). We used human cerebellar tissues obtained at autopsy from three PCD with LEMS patients and six other disease patients including one with LEMS as the controls. We compared cerebellar P/Q-type VGCC in these patients and controls for the amount and ratio of autoantibody-channel complex using an _<125>I-w-conotoxin MVIIC binding assay with Scatchard analysis, and their distribution using autoradiography. The quantity of cerebellar P/Q-type VGCC measured by Scatchard analysis were reduced in PCD with LEMS patients (63.0±7.0 fmol/mg, n=3), compared with the controls (297.8±38.9 fmol/mg, n=6). The ratio of autoantibody-VGCC complexes to total P/Q-type VGCC measured by immunoprecipitation assay were increased in PCD-LEMS patients. We analysed the autoradiographic image of cerebellar specimens using ^<125>I-ω-conotoxin MVIIC, which specifically binds to P/Q-type VGCC. In PCD-LEMS cerebellum, the toxin binding sites of P/Q-type VGCC were markedly reduced compared to control specimens, especially in the molecular layer which is the richest area of P/Q-type VGCC in the normal cerebellum. These results suggest that P/Q-type VGCC of the cerebellar molecular layer is the immunological target in developing PCD with LEMS.

本研究的目的是阐明小脑P/ q型电压门控钙通道（VGCC）的自身免疫是否与副肿瘤小脑变性（PCD）合并Lambert-Eaton肌无力综合征（LEMS）的发病机制有关。我们使用尸检中获得的人类小脑组织，这些组织来自三名患有LEMS的PCD患者和六名其他疾病患者，其中包括一名LEMS患者。我们采用_<125> i -w- concontoxin MVIIC结合试验和Scatchard分析比较了这些患者和对照组小脑P/ q型VGCC的自身抗体-通道复合物的数量和比例，并使用放射自显影术比较了它们的分布。经Scatchard分析，PCD合并LEMS患者小脑P/ q型VGCC含量（63.0±7.0 fmol/mg, n=3）低于对照组（297.8±38.9 fmol/mg, n=6）。免疫沉淀法测定PCD-LEMS患者自身抗体-VGCC复合物与总P/ q型VGCC的比值升高。我们使用^<125>I-ω-conotoxin MVIIC分析了小脑标本的放射自显影图像，它特异性地结合P/ q型VGCC。在PCD-LEMS小脑中，P/ q型VGCC的毒素结合位点明显减少，特别是在正常小脑中P/ q型VGCC最丰富的分子层。提示小脑分子层P/ q型VGCC是LEMS合并PCD发生的免疫靶点。

项目成果

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