跨脑部疾病的转录组脆弱性单细胞图谱
Single-cell atlas of transcriptomic vulnerability across brain disorders
研究想弄清阿尔茨海默病、帕金森病、精神分裂症等复杂脑病的分子机制。作者用1494名供者的脑组织（背外侧前额叶皮层）构建了超过630万个细胞核的单细胞转录组图谱，覆盖八种脑病与健康对照。结果发现个体间差异占基因表达变异的很大部分，扣除跨疾病共性信号后，阿尔茨海默病、弥漫性路易体病、血管性痴呆和帕金森病之间遗传与表达一致性更强。研究还发现重度阿尔茨海默病患者神经元减少、免疫与血管细胞增多，为治疗靶点提供线索。
为什么推荐给您：大规模人群尺度单细胞图谱，揭示脑病共享与特异机制，属重要新数据资源。
不需要生物学背景，多打比方
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摘要Abstract
Neurodegenerative and neuropsychiatric diseases impose a considerable societal and public health burden. However, our understanding of the molecular mechanisms underlying these highly complex conditions remains limited1,2. Here, to gain deeper insights into the aetiology of different brain diseases, we used specimens from 1,494 unique donors to generate a population-scale single-cell transcriptomic atlas of the human dorsolateral prefrontal cortex, comprising over 6.3 million individual nuclei. The cohort includes neurotypical controls, as well as donors affected by eight common and complex brain disorders: Alzheimer's disease (AD), diffuse Lewy body disease (DLBD), vascular dementia (Vas), Parkinson's disease (PD), tauopathy, frontotemporal dementia, schizophrenia, and bipolar disorder. We show that interindividual variation accounts for a substantial portion of gene expression variation. By comparing transcriptomic variation across diseases, we reveal universal signatures enriched in basic cellular functions such as mRNA processing and protein localization. After discounting these cross-disease signatures, we show stronger genetic and transcriptomic concordance among AD, DLBD, Vas and PD. Furthermore, we characterize transcriptomic variation among different AD phenotypes, distinct from those observed in healthy ageing, revealing a reduction in neuronal abundance in individuals with more severe AD, coupled with an increase in immune and vascular cell populations. Exploring the neuropsychiatric symptoms (NPSs) that frequently accompany AD, we find an increased abundance of deep-layer excitatory neurons associated with a broad range of NPSs. By constructing transcriptome trajectories that capture AD progression, we implicate cell-type-specific responses in the early and late stages of AD. Our disease atlas provides a perspective of the transcriptomic landscape in neurodegenerative and neuropsychiatric disorders, shedding light on shared and distinct processes involving the neurological-immune-vascular systems, and identifying potential targets for therapeutic intervention.