Alpha-synuclein seeding shows a wide heterogeneity in multiple system atrophy.
Alpha-synuclein seeding shows a wide heterogeneity in multiple system atrophy.
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DOI：
10.1186/s40035-022-00283-4
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发表时间：
2022-02-07
影响因子：
12.6
通讯作者：
Kovacs GG
中科院分区：
文献类型：
--
作者：
Martinez-Valbuena I;Visanji NP;Kim A;Lau HHC;So RWL;Alshimemeri S;Gao A;Seidman MA;Luquin MR;Watts JC;Lang AE;Kovacs GG
多系统萎缩(MSA)是一种神经退行性疾病，其特征是帕金森氏症、自主神经衰竭、小脑性共济失调和锥体特征的各种组合。虽然突触核病的分布与主要的临床特征相关，但病理负担并不能完全解释临床表现和疾病进展速度的差异。我们假设，多发性硬化的临床异质性是不同患者之间和不同脑区之间α-突触核蛋白种子活性差异的结果。使用无细胞扩增方法可靠地检测α来源的突触核蛋白种子活性仍然具有挑战性。因此，我们对168种不同的反应缓冲液进行了系统的评估，使用了一组pH和盐，种子来自一名MSA和一名PD患者的完全特征化的脑匀浆。然后，我们在40例神经病理确诊病例(包括15例MSA)的较大队列中验证了两种条件，这两种条件赋予了区分PD和MSA来源样本的最佳能力。最后，在大脑的一个子集中，我们对MSA中的播种行为进行了第一次多区域分析。使用我们新的缓冲条件，我们证明了控制α-突触核蛋白体外扩增的物理化学因素可以被定制来产生菌株特异性的反应缓冲液，可以用于可靠地研究来自α-突触核蛋白的种子能力。使用这种新的方法，我们能够将15个MSA大脑细分为3组：高、中和低播种者。为了进一步证明在多年生种质资源中α同步核蛋白播种的异质性，我们对13个不同地区的α同步核蛋白播种进行了综合的多区域评估，这些种子来自2个高播种者、2个中播者和2个低播种者。我们已经在一组神经病理上具有可比性的大脑中发现了种子能力α-突触核蛋白的意想不到的差异。此外，我们的工作揭示了播种活动的实质性异质性，这是由可溶于铅的α-突触核蛋白驱动的，在给定个体的不同大脑区域之间，这超出了免疫组织化学的观察。我们的观察为未来的MSA亚型铺平了道路，这种亚型超过了传统的临床和神经病理表型，并考虑了目前α-突触核蛋白的结构和生化异质性。最后，我们的方法为发展急需的、快速和灵敏的MSA诊断方法提供了一个实验框架。网上版载有补充材料，可在10.1186/s40035-022-022-4查阅。
Multiple system atrophy (MSA) is a neurodegenerative condition characterized by variable combinations of parkinsonism, autonomic failure, cerebellar ataxia and pyramidal features. Although the distribution of synucleinopathy correlates with the predominant clinical features, the burden of pathology does not fully explain observed differences in clinical presentation and rate of disease progression. We hypothesized that the clinical heterogeneity in MSA is a consequence of variability in the seeding activity of α-synuclein both between different patients and between different brain regions. The reliable detection of α-synuclein seeding activity derived from MSA using cell-free amplification assays remains challenging. Therefore, we conducted a systematic evaluation of 168 different reaction buffers, using an array of pH and salts, seeded with fully characterized brain homogenates from one MSA and one PD patient. We then validated the two conditions that conferred the optimal ability to discriminate between PD- and MSA-derived samples in a larger cohort of 40 neuropathologically confirmed cases, including 15 MSA. Finally, in a subset of brains, we conducted the first multi-region analysis of seeding behaviour in MSA. Using our novel buffer conditions, we show that the physicochemical factors that govern the in vitro amplification of α-synuclein can be tailored to generate strain-specific reaction buffers that can be used to reliably study the seeding capacity from MSA-derived α-synuclein. Using this novel approach, we were able to sub-categorize the 15 MSA brains into 3 groups: high, intermediate and low seeders. To further demonstrate heterogeneity in α-synuclein seeding in MSA, we conducted a comprehensive multi-regional evaluation of α-synuclein seeding in 13 different regions from 2 high seeders, 2 intermediate seeders and 2 low seeders. We have identified unexpected differences in seed-competent α-synuclein across a cohort of neuropathologically comparable MSA brains. Furthermore, our work has revealed a substantial heterogeneity in seeding activity, driven by the PBS-soluble α-synuclein, between different brain regions of a given individual that goes beyond immunohistochemical observations. Our observations pave the way for future subclassification of MSA, which exceeds conventional clinical and neuropathological phenotyping and considers the structural and biochemical heterogeneity of α-synuclein present. Finally, our methods provide an experimental framework for the development of vitally needed, rapid and sensitive diagnostic assays for MSA. The online version contains supplementary material available at 10.1186/s40035-022-00283-4.
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多个系统衰老相关的tau星形胶质细胞病，具有复杂的蛋白质病，在寡症状的八十岁室中。
DOI：
10.1111/neup.12708
发表时间：
2021-03
期刊：
Neuropathology : official journal of the Japanese Society of Neuropathology
影响因子：
--
作者：
Klotz S;Fischer P;Hinterberger M;Ricken G;Hönigschnabl S;Gelpi E;Kovacs GG
通讯作者：
Kovacs GG
影响因子：
4.7
作者：
Campbell, BCV;McLean, CA;Li, QX
通讯作者：
Li, QX
影响因子：
29
作者：
Bongianni, Matilde;Orru, Christina;Zanusso, Gianluigi
通讯作者：
Zanusso, Gianluigi
影响因子：
4.4
作者：
PAPP, MI;KAHN, JE;LANTOS, PL
通讯作者：
LANTOS, PL
影响因子：
14.8
作者：
Schmitz, Matthias;Cramm, Maria;Zerr, Inga
通讯作者：
Zerr, Inga