α-synucleinopathies are progressive neurodegenerative disorders characterized by intracellular aggregation of α-synuclein, yet their molecular pathogenesis remains unknow. Here, we explore cell-specific changes in gene expression across different α-synucleinopathies. We perform single-nucleus RNA sequencing on nearly 300,000 nuclei from the prefrontal cortex of individuals with idiopathic Parkinson’s disease (iPD, n = 20), Parkinson’s disease caused by LRRK2 mutations (LRRK2-PD, n = 7), multiple system atrophy (MSA, n = 6) and healthy controls (n = 13). iPD and LRRK2-PD exhibit a largely overlapping cell type-specific signature, which is distinct from that of MSA, and includes an overall decrease of the transcriptional output in neurons. Notably, most of the differential expression signal in iPD and LRRK2-PD is concentrated in a specific deep cortical neuronal subtype expressing adrenoceptor alpha 2A. While most differentially expressed genes are highly cell type- and disease-specific, PDE10A is found consistently downregulated in most cortical neurons, and across all three diseases. Finally, exploiting the variable presence and/or severity of α-synuclein pathology in LRRK2-PD and iPD, we identify cell type-specific signatures associated with α-synuclein pathology, including a neuronal upregulation of the SNCA gene itself, encoding α-synuclein. Our findings provide novel insights into the cell-specific transcriptional landscape of the α-synucleinopathy spectrum.

中文翻译：

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单核转录组学揭示了 α-突触核蛋白病的疾病和病理特异性特征


α-突触核蛋白病是一种进行性神经退行性疾病，其特征是 α-突触核蛋白在细胞内聚集，但其分子发病机制尚不清楚。在这里，我们探讨了不同 α-突触核蛋白病中基因表达的细胞特异性变化。我们对特发性帕金森病 （iPD， n = 20）、LRRK2 突变引起的帕金森病 （LRRK2-PD， n = 7）、多系统萎缩 （MSA， n = 6） 和健康对照 （n = 13） 患者的前额叶皮层的近 300,000 个细胞核进行了单核 RNA 测序。iPD 和 LRRK2-PD 表现出在很大程度上重叠的细胞类型特异性特征，这与 MSA 不同，包括神经元转录输出的整体减少。值得注意的是，iPD 和 LRRK2-PD 中的大部分差异表达信号集中在表达肾上腺素能受体 α 2A 的特定深皮层神经元亚型中。虽然大多数差异表达基因具有高度的细胞类型和疾病特异性，但 PDE10A 在大多数皮层神经元和所有三种疾病中都被发现持续下调。最后，利用 LRRK2-PD 和 iPD 中 α-突触核蛋白病理学的可变存在和/或严重程度，我们确定了与 α-突触核蛋白病理学相关的细胞类型特异性特征，包括编码 α-突触核蛋白的 SNCA 基因本身的神经元上调。我们的研究结果为 α-突触核蛋白病谱系的细胞特异性转录景观提供了新的见解。