Disease-, region- and cell type specific diversity of α-synuclein carboxy terminal truncations in synucleinopathies.
Disease-, region- and cell type specific diversity of α-synuclein carboxy terminal truncations in synucleinopathies.
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DOI：
10.1186/s40478-021-01242-2
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发表时间：
2021-08-28
影响因子：
7.1
通讯作者：
Giasson BI
中科院分区：
文献类型：
--
作者：
Hass EW;Sorrentino ZA;Xia Y;Lloyd GM;Trojanowski JQ;Prokop S;Giasson BI
突触核蛋白病，包括帕金森病（PD）、路易体痴呆（LBD）、阿尔茨海默病伴杏仁核限制性路易体（AD/ALB）和多系统萎缩（MSA），包括一系列神经退行性疾病，其特征在于存在不同的病理性α-突触核蛋白（αSyn）包涵体。实验和病理学研究支持以下观点：αSyn聚集体通过构象模板作用导致细胞死亡和功能障碍，疾病进展与αSyn聚集体的朊病毒样扩散相关。导致不同形式的突触核蛋白病的起始事件和因素仍然知之甚少。与病理性包涵体相关的αSyn的主要翻译后修饰是羧基末端区域内的多种特异性截短。虽然这些修饰已在实验上显示出诱导和促进αSyn聚集，但对其疾病、区域和细胞类型特异性分布知之甚少。为此，我们产生了一系列特异性针对αSyn中在残基103、115、119、122、125和129后截短的新表位的单克隆抗体。使用这些新工具进行的免疫细胞化学研究显示，不同突触核蛋白病、脑区和特定细胞群体之间的αSyn截短模式存在显著差异。在LBD中，黑质和杏仁核中的神经元内含物在残基103，119，122和125后裂解的αSyn呈阳性，但不是115。而在同一患者的脑中，αSyn在残基115处裂解，在迷走神经背侧运动核中，αSyn在残基103、119和122处裂解丰富。在AD/ALB患者中，这些修饰在杏仁核αSyn包涵体中仅微弱或未检测到。在残基103、115、119和125处截短的αSyn容易存在于MSA胶质细胞胞质内含物中，但122切割的αSyn仅微弱存在或不存在。相反，脑桥核中的MSA神经元病理学对αSyn x-122新表位具有强烈反应性，但对αSyn 103裂解没有显示任何反应性。这些研究表明，与病理性包涵体相关的羧基末端αSyn加工存在显著的疾病、区域和细胞类型特异性差异，这可能有助于其独特的毒株样朊病毒特性，并促进这些隐伏疾病程度的多样性。在线版本包含补充材料，可通过10.1186/s40478-021-01242-2获得。
Synucleinopathies, including Parkinson’s disease (PD), Lewy body dementia (LBD), Alzheimer’s disease with amygdala restricted Lewy bodies (AD/ALB), and multiple system atrophy (MSA) comprise a spectrum of neurodegenerative disorders characterized by the presence of distinct pathological α-synuclein (αSyn) inclusions. Experimental and pathological studies support the notion that αSyn aggregates contribute to cellular demise and dysfunction with disease progression associated with a prion-like spread of αSyn aggregates via conformational templating. The initiating event(s) and factors that contribute to diverse forms of synucleinopathies remain poorly understood. A major post-translational modification of αSyn associated with pathological inclusions is a diverse array of specific truncations within the carboxy terminal region. While these modifications have been shown experimentally to induce and promote αSyn aggregation, little is known about their disease-, region- and cell type specific distribution. To this end, we generated a series of monoclonal antibodies specific to neo-epitopes in αSyn truncated after residues 103, 115, 119, 122, 125, and 129. Immunocytochemical investigations using these new tools revealed striking differences in the αSyn truncation pattern between different synucleinopathies, brain regions and specific cellular populations. In LBD, neuronal inclusions in the substantia nigra and amygdala were positive for αSyn cleaved after residues 103, 119, 122, and 125, but not 115. In contrast, in the same patients' brain αSyn cleaved at residue 115, as well as 103, 119 and 122 were abundant in the dorsal motor nucleus of the vagus. In patients with AD/ALB, these modifications were only weakly or not detected in amygdala αSyn inclusions. αSyn truncated at residues 103, 115, 119, and 125 was readily present in MSA glial cytoplasmic inclusions, but 122 cleaved αSyn was only weakly or not present. Conversely, MSA neuronal pathology in the pontine nuclei was strongly reactive to the αSyn x-122 neo-epitope but did not display any reactivity for αSyn 103 cleavage. These studies demonstrate significant disease-, region- and cell type specific differences in carboxy terminal αSyn processing associated with pathological inclusions that likely contributes to their distinct strain-like prion properties and promotes the diversity displayed in the degrees of these insidious diseases. The online version contains supplementary material available at 10.1186/s40478-021-01242-2.
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影响因子：
8.6
作者：
Appel-Cresswell, Silke;Vilarino-Guell, Carles;Farrer, Matthew J.
通讯作者：
Farrer, Matthew J.
影响因子：
4.7
作者：
Campbell, BCV;McLean, CA;Li, QX
通讯作者：
Li, QX
影响因子：
168.9
作者：
Chartier-Harlin, MC;Kachergus, J;Destée, A
通讯作者：
Destée, A
在GBA-N370S帕金森氏菌IPSC衍生的多巴胺神经元中，ER应力和自噬扰动导致细胞外α-突触核蛋白升高。
影响因子：
5.9
作者：
Fernandes HJ;Hartfield EM;Christian HC;Emmanoulidou E;Zheng Y;Booth H;Bogetofte H;Lang C;Ryan BJ;Sardi SP;Badger J;Vowles J;Evetts S;Tofaris GK;Vekrellis K;Talbot K;Hu MT;James W;Cowley SA;Wade-Martins R
通讯作者：
Wade-Martins R
影响因子：
2.9
作者：
DUNN, SD
通讯作者：
DUNN, SD