Pallidonigral TDP-43 pathology in Perry syndrome
Pallidonigral TDP-43 pathology in Perry syndrome
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DOI：
10.1016/j.parkreldis.2008.07.005
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发表时间：
2009-05-01
影响因子：
4.1
通讯作者：
Wszolek, Zbigniew K.
中科院分区：
文献类型：
--
作者：
Wider, Christian;Dickson, Dennis W.;Wszolek, Zbigniew K.
目的：常染色体显性遗传性帕金森综合征(Perry综合征)是一种起病早、进展快的疾病。在尸检中，先前的研究已经发现在黑质中没有路易小体的严重神经元丢失。最近发现，43 kDa的反式反应DNA结合蛋白(TDP-43)是额颞叶变性伴泛素阳性包涵体和肌萎缩侧索硬化症中神经元和神经胶质包涵体的主要泛素化成分。本研究报告了Perry综合征的临床、遗传学和神经病理学研究。方法：收集来自4个家系无关的Perry综合征家系的8例患者的临床资料和尸检脑组织标本。用免疫组织化学和生化方法检测脑组织中TDP-43的表达。结果：平均发病年龄47岁(40~56岁)，平均死亡年龄52岁(44~)。在所有患者中，我们发现以苍白球为主的TDP-43阳性神经元包涵体、营养不良的轴突和轴突球体，我们发现TDP-43在脑组织中的溶解性和电泳率发生了变化。包涵体高度多形性，主要分布在锥体外系，皮质、海马区和运动神经元较少。GRN或TARDBP.没有突变。解释：Perry综合征表现出独特的TDP-43病理，该病理对锥体外系具有选择性，而不涉及新皮质和运动神经元。(C)2008爱思唯尔有限公司。保留所有权利。
Objective: Autosomal dominant parkinsonism, hypoventilation, depression and severe weight loss (Perry syndrome) is an early-onset rapidly progressive disease. At autopsy, previous studies have found severe neuronal loss in the substantia nigra without Lewy bodies. Transactive response DNA-binding protein of 43 kDa (TDP-43) has recently been identified as a major ubiquitinated constituent of neuronal and glial inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis. This study reports clinical, genetic and neuropathologic investigations of Perry syndrome.Methods: Clinical data and autopsy brain tissue samples were collected from eight patients from four genealogically unrelated kindreds with Perry syndrome. Brain tissue was studied with immunohistochemistry and biochemistry for TDP-43. Patients were screened for mutations in the progranulin (GRN) and TDP-43 (TARDBP) genes.Results: The mean age at onset was 47 years (range 40-56), and the mean age at death was 52 years (range 44-64). In all patients, we identified TDP-43-positive neuronal inclusions, dystrophic neurites and axonal spheroids in a predominantly pallidonigral distribution, and we demonstrated changes in solubility and electrophoretic mobility of TDP-43 in brain tissue. The inclusions were highly pleomorphic and predominated in the extrapyramidal system, sparing the cortex, hippocampus and motor neurons. There were no mutations in GRN or TARDBP.Interpretation: Perry syndrome displays unique TDP-43 pathology that is selective for the extrapyramidal system and spares the neocortex and motor neurons. (C) 2008 Elsevier Ltd. All rights reserved.