Synucleinopathies are mostly sporadic neurodegenerative disorders of partly unexplained aetiology, and include Parkinson's disease (PD) and multiple system atrophy (MSA). We have further investigated our recent finding of somatic SNCA (α-synuclein) copy number variants (CNVs, specifically gains) in synucleinopathies, using Fluorescent in-situ Hybridisation for SNCA, and single-cell whole genome sequencing for the first time in a synucleinopathy. In the cingulate cortex, mosaicism levels for SNCA gains were higher in MSA and PD than controls in neurons (> 2% in both diseases), and for MSA also in non-neurons. In MSA substantia nigra (SN), we noted SNCA gains in > 3% of dopaminergic (DA) neurons (identified by neuromelanin) and neuromelanin-negative cells, including olig2-positive oligodendroglia. Cells with CNVs were more likely to have α-synuclein inclusions, in a pattern corresponding to cell categories mostly relevant to the disease: DA neurons in Lewy-body cases, and other cells in the striatonigral degeneration-dominant MSA variant (MSA-SND). Higher mosaicism levels in SN neuromelanin-negative cells may correlate with younger onset in typical MSA-SND, and in cingulate neurons with younger death in PD. Larger sample sizes will, however, be required to confirm these putative findings. We obtained genome-wide somatic CNV profiles from 169 cells from the substantia nigra of two MSA cases, and pons and putamen of one. These showed somatic CNVs in ~ 30% of cells, with clonality and origins in segmental duplications for some. CNVs had distinct profiles based on cell type, with neurons having a mix of gains and losses, and other cells having almost exclusively gains, although control data sets will be required to determine possible disease relevance. We propose that somatic SNCA CNVs may contribute to the aetiology and pathogenesis of synucleinopathies, and that genome-wide somatic CNVs in MSA brain merit further study.

中文翻译：

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使用靶向 SNCA 分析和单细胞测序研究突触核蛋白病病例大脑中的体细胞 CNV。

突触核蛋白病大多是部分病因不明的散发性神经退行性疾病，包括帕金森病 (PD) 和多系统萎缩症 (MSA)。我们进一步研究了最近在突触核蛋白病中发现的体细胞 SNCA（α-突触核蛋白）拷贝数变异（CNV，特别是增益），使用 SNCA 荧光原位杂交，并首次在突触核蛋白病中进行了单细胞全基因组测序。在扣带皮层中，MSA 和 PD 中神经元中 SNCA 增益的镶嵌水平高于对照（两种疾病中均 > 2%），非神经元中的 MSA 增益镶嵌水平也更高。在 MSA 黑质 (SN) 中，我们注意到超过 3% 的多巴胺能 (DA) 神经元（由神经黑色素识别）和神经黑色素阴性细胞（包括 olig2 阳性少突神经胶质细胞）中 SNCA 增加。具有 CNV 的细胞更有可能具有 α-突触核蛋白内含物，其模式对应于与疾病最相关的细胞类别：路易体病例中的 DA 神经元，以及纹状体黑质变性为主的 MSA 变体 (MSA-SND) 中的其他细胞。SN 神经黑色素阴性细胞中较高的嵌合水平可能与典型 MSA-SND 中较年轻的发病相关，以及在 PD 中较年轻死亡的扣带神经元中的较高镶嵌水平。然而，需要更大的样本量来证实这些假定的发现。我们从两个 MSA 病例的黑质以及 1 个病例的脑桥和壳核的 169 个细胞中获得了全基因组体细胞 CNV 谱。这些显示约 30% 的细胞中存在体细胞 CNV，其中一些细胞具有克隆性和片段重复起源。CNV 根据细胞类型具有不同的特征，神经元有增益和损失的混合，而其他细胞几乎完全有增益，尽管需要控制数据集来确定可能的疾病相关性。我们认为体细胞 SNCA CNV 可能有助于突触核蛋白病的病因学和发病机制，并且 MSA 大脑中的全基因组体细胞 CNV 值得进一步研究。