Prion-like propagation of human brain-derived alpha-synuclein in transgenic mice expressing human wild-type alpha-synuclein.
Prion-like propagation of human brain-derived alpha-synuclein in transgenic mice expressing human wild-type alpha-synuclein.
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DOI：
10.1186/s40478-015-0254-7
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发表时间：
2015-11-26
影响因子：
7.1
通讯作者：
Tamgüney G
中科院分区：
文献类型：
--
作者：
Bernis ME;Babila JT;Breid S;Wüsten KA;Wüllner U;Tamgüney G
帕金森病（PD）和多系统萎缩（MSA）是以含有聚集体的α-突触核蛋白的细胞内积累为特征的神经退行性疾病。最近越来越多的证据表明，帕金森氏病和MSA病理学传播整个神经系统的时空方式，可能是通过朊病毒样传播的α-突触核蛋白阳性聚集体之间的突触连接的区域。同时，将病理性α-突触核蛋白脑内注射到过表达人野生型α-突触核蛋白或具有家族性A53 T突变的人α-突触核蛋白的转基因小鼠中或注射到野生型小鼠中导致α-突触核蛋白病理在CNS中扩散。考虑到野生型小鼠天然地也在α-突触核蛋白的密码子53处表达苏氨酸，仍然不清楚在不存在内源表达的小鼠α-突触核蛋白的情况下，单独的人野生型α-突触核蛋白是否将支持α-突触核蛋白病理学在体内的类似传播。在这里，我们表明，脑提取物从两名患者MSA和两名患者可能偶发路易体病（iLBD），但不是磷酸盐缓冲盐水诱导朊病毒样传播的病理性α-突触核蛋白后，纹状体内注射到小鼠表达人类野生型α-突触核蛋白。在注射后3、6和9个月处死小鼠，并进行神经病理学和生物化学分析。注射来自患有MSA或可能的iLBD的患者的脑提取物的小鼠都积累了神经元内包涵体，其对磷酸化α-突触核蛋白染色呈阳性，并且在6个月后主要出现在注射的脑半球内。9个月后，这些神经元内包涵体已扩散到对侧半球和更多的吻侧和尾侧区域。生物化学分析显示，注射了来自患有MSA和可能的iLBD的患者的脑提取物的小鼠的脑含有过度磷酸化的α-突触核蛋白，其也在硫磺素T结合测定中接种了重组人野生型α-突触核蛋白的聚集。我们的研究结果表明，人类野生型α-突触核蛋白支持朊病毒样传播的α-突触核蛋白病理在体内内源性表达的小鼠α-突触核蛋白的情况下。本文的在线版本（doi：10.1186/s40478-015-0254-7）包含补充材料，可供授权用户使用。
Parkinson’s disease (PD) and multiple system atrophy (MSA) are neurodegenerative diseases that are characterized by the intracellular accumulation of alpha-synuclein containing aggregates. Recent increasing evidence suggests that Parkinson’s disease and MSA pathology spread throughout the nervous system in a spatiotemporal fashion, possibly by prion-like propagation of alpha-synuclein positive aggregates between synaptically connected areas. Concurrently, intracerebral injection of pathological alpha-synuclein into transgenic mice overexpressing human wild-type alpha-synuclein, or human alpha-synuclein with the familial A53T mutation, or into wild-type mice causes spreading of alpha-synuclein pathology in the CNS. Considering that wild-type mice naturally also express a threonine at codon 53 of alpha-synuclein, it has remained unclear whether human wild-type alpha-synuclein alone, in the absence of endogenously expressed mouse alpha-synuclein, would support a similar propagation of alpha-synuclein pathology in vivo. Here we show that brain extracts from two patients with MSA and two patients with probable incidental Lewy body disease (iLBD) but not phosphate-buffered saline induce prion-like spreading of pathological alpha-synuclein after intrastriatal injection into mice expressing human wild-type alpha-synuclein. Mice were sacrificed at 3, 6, and 9 months post injection and analyzed neuropathologically and biochemically. Mice injected with brain extracts from patients with MSA or probable iLBD both accumulated intraneuronal inclusion bodies, which stained positive for phosphorylated alpha-synuclein and appeared predominantly within the injected brain hemisphere after 6 months. After 9 months these intraneuronal inclusion bodies had spread to the contralateral hemisphere and more rostral and caudal areas. Biochemical analysis showed that brains of mice injected with brain extracts from patients with MSA and probable iLBD contained hyperphosphorylated alpha-synuclein that also seeded aggregation of recombinant human wild-type alpha-synuclein in a Thioflavin T binding assay. Our results indicate that human wild-type alpha-synuclein supports the prion-like spreading of alpha-synuclein pathology in the absence of endogenously expressed mouse alpha-synuclein in vivo. The online version of this article (doi:10.1186/s40478-015-0254-7) contains supplementary material, which is available to authorized users.