NUCLEAR AND NEURITIC DISTRIBUTION OF SERINE-129 PHOSPHORYLATED α-SYNUCLEIN IN TRANSGENIC MICE
NUCLEAR AND NEURITIC DISTRIBUTION OF SERINE-129 PHOSPHORYLATED α-SYNUCLEIN IN TRANSGENIC MICE
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DOI：
10.1016/j.neuroscience.2009.03.002
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发表时间：
2009-06-02
期刊：
影响因子：
3.3
通讯作者：
Kahle, P. J.
中科院分区：
文献类型：
--
作者：
Schell, H.;Hasegawa, T.;Kahle, P. J.
帕金森氏病和路易体痴呆是老年人常见的神经系统疾病。阿尔法-突触核蛋白(α-SYN)基因突变会导致帕金森氏症，通常与痴呆症有关。在神经病理学上，这些疾病的特点是存在路易小体和路易神经突起，神经元内的包涵体主要由α-SYN蛋白纤维组成。此外，在神经病理损伤中，αSYN在S129(磷酸丝氨酸-129[PSer129])处被磷酸化。使用我们的(Thy1)-[A30P]αSYN转基因小鼠在恐惧条件性行为中出现年龄相关性损害的模型，我们研究了PSer129在大脑中的免疫染色。我们使用新的、敏感的单抗发现了不同的染色模式。随着年龄的增长，在海马区和皮质区以及杏仁外侧核和基底外侧核中，胞体和核的PSer129免疫反应增加，在年轻的无症状的小鼠中也存在，但不存在野生型对照。在细胞培养中证实了PSer129免疫染色在细胞核内积聚的趋势。(Thy1)-[A30P]αSYN转基因小鼠在杏仁中央核的内侧部分及其投射区域之一--下丘脑外侧进一步发展了年龄依赖的特异性神经炎/终末αSYN病理。有趣的是，这种类型的PSer129神经病理是硫代黄素S阴性的，不像(Thy1)[A30P]αSYN小鼠脑干中存在的路易样神经病理。因此，在这个阿尔法突触核病小鼠模型中，阿尔法SYN在大脑的不同部分变得磷酸化，显示出大脑皮质区域PSer129核的年龄相关性增加，并形成神经性/终末性PSer129神经病理，在恐惧条件反射回路和脑干内淀粉样蛋白质量可变。(C)2009年IBRO。爱思唯尔有限公司出版。保留所有权利。
Parkinson's disease and dementia with Lewy bodies are very frequent neurological disorders of the elderly. Mutations in the alpha-synuclein (alpha SYN) gene cause Parkinson's disease, often associated with dementia. Neuropathologically these diseases are characterized by the presence of Lewy bodies and Lewy neurites, intraneuronal inclusions mostly composed of alpha SYN protein fibrils. Moreover, alpha SYN is phosphorylated at S129 (phospho-serine-129 [PSer129]) in neuropathological lesions. Using our (Thy1)-[A30P]alpha SYN transgenic mouse model that develops age-dependent impairment in fear conditioning behavior, we investigated PSer129 immunostaining in the brain. We found distinct staining patterns using new, sensitive monoclonal antibodies. Somal and nuclear PSer129 immunoreactivity increased with age in hippocampal and cortical areas as well as the lateral/basolateral amygdalar nuclei and was present also in young, pre-symptomatic mice, but not wild-type controls. The tendency of PSer129 immunostaining to accumulate in the nucleus was confirmed in cell culture. (Thy1)-[A30P]alpha SYN transgenic mice further developed age-dependent, specific neuritic/terminal alpha SYN pathology in the medial parts of the central amygdalar nucleus and one of its projection areas, the lateral hypothalamus. Interestingly, this type of PSer129 neuropathology was thioflavine S negative, unlike the Lewy-like neuropathology present in the brain stem of (Thy1)[A30P]alpha SYN mice. Thus, alpha SYN becomes phosphorylated in distinct parts of the brain in this alpha-synucleinopathy mouse model, showing age-dependent increases of nuclear PSer129 in cortical brain areas and the formation of neuritic/terminal PSer129 neuropathology with variable amyloid quality within the fear conditioning circuitry and the brain stem. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved.