使用高效单细胞核RNA测序（HIF-snRNA-seq）剖析帕金森病和帕金森病痴呆的分子格局。

Dissecting the molecular landscape of Parkinson's disease and Parkinson's disease dementia using highly efficient snRNA-seq (HIF-snRNA-seq).

作者信息

Kang Sung-Ung, Park Jinhee, Ha Shinwon, Kim Dongsan, Pletnikova Olga, Redding-Ochoa Javier, Troncoso Juan C, Peng Quan, Van Emburgh Beth O, Trivedi Jaldhir, Brahmachari Saurav, Nezami Bardia, Dawson Valina L, Dawson Ted M

机构信息

Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205 USA.

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205 USA.

出版信息

bioRxiv. 2025 Mar 7:2025.03.01.640894. doi: 10.1101/2025.03.01.640894.

DOI:10.1101/2025.03.01.640894

PMID:40093124

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11908213/

Abstract

This study presents a transcriptomic analysis of the cingulate cortex (CING) in Parkinson's disease (PD) and Parkinson's disease dementia (PDD) using a High-efficiency single-nucleus RNA sequencing (HiF-snRNA-seq) protocol optimized for post-mortem brain samples. RNA quality prediction, poly-A tailing, and dCas9-targeted depletion enabled analysis of 77 high-quality samples from 240 cases, yielding over 2 million nuclei classified into seven major cell types. Disease conditions revealed altered astrocyte and microglia proportions, implicating their roles in neuroinflammation. Differential expression analysis identified unique and shared genes across PD and PDD, linked to synaptic remodeling, stress responses, and inflammation. Stage-specific analysis uncovered tau-dependent early-stage genes and inflammation-associated late-stage genes. This study highlights the CING's central role in PD and PDD pathophysiology, offering insights into disease mechanisms and identifying candidate genes and pathways for therapeutic and biomarker development.

摘要

本研究使用针对尸检脑样本优化的高效单核RNA测序（HiF-snRNA-seq）方案，对帕金森病（PD）和帕金森病痴呆（PDD）患者的扣带回皮质（CING）进行了转录组分析。RNA质量预测、多聚腺苷酸化加尾和dCas9靶向缺失使得能够对来自240例患者的77个高质量样本进行分析，产生了超过200万个被分类为七种主要细胞类型的细胞核。疾病状态显示星形胶质细胞和小胶质细胞比例发生改变，提示它们在神经炎症中的作用。差异表达分析确定了PD和PDD中独特和共有的基因，这些基因与突触重塑、应激反应和炎症有关。阶段特异性分析揭示了tau依赖性早期基因和炎症相关晚期基因。本研究突出了扣带回皮质在PD和PDD病理生理学中的核心作用，为疾病机制提供了见解，并为治疗和生物标志物开发鉴定了候选基因和途径。