Single-nucleus analysis reveals oxidative stress in Down syndrome basal forebrain neurons at birth.

bioRxiv : the preprint server for biology Pub Date : 2025-06-12 DOI:10.1101/2025.02.05.636750

Nicole R West, Kalpana Hanthanan Arachchilage, Sara Knaack, Shawn MacGregor, Masoumeh Hosseini, Ryan D Risgaard, Pubudu Kumarage, Jose L Martinez, Su-Chun Zhang, Daifeng Wang, Andre M M Sousa, Anita Bhattacharyya

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Abstract

Introduction: Basal forebrain cholinergic neurons (BFCNs) are integral to learning, attention, and memory, and are prone to degeneration in Down syndrome (DS), Alzheimer's disease, and other neurodegenerative diseases. However, the mechanisms that lead to the degeneration of these neurons are not known.

Methods: Single-nucleus gene expression and ATAC sequencing were performed on postmortem human basal forebrain from unaffected control and DS tissue samples at 0-2 years of age (n=4 each).

Results: Sequencing analysis of postmortem human basal forebrain identifies gene expression differences in DS early in life. Genes encoding proteins associated with energy metabolism pathways, specifically oxidative phosphorylation and glycolysis, and genes encoding antioxidant enzymes are upregulated in DS BFCNs.

Discussion: Multiomic analyses reveal that energy metabolism may be disrupted in DS BFCNs by birth. Increased oxidative phosphorylation and the accumulation of reactive oxygen species byproducts may be early contributors to DS BFCN neurodegeneration.

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单核分析揭示出生时唐氏综合征基底前脑氧化磷酸化失调。

导言：基底前脑胆碱能神经元（BFCNs）是学习、注意力和记忆不可或缺的神经元，在唐氏综合征（DS）、阿尔茨海默病和其他神经退行性疾病中易发生变性。然而，导致这些神经元退化的机制尚不清楚：方法：对 0-2 岁未受影响的对照组和 DS 组织样本（各 4 个）的人类死后基底前脑进行单核基因表达和 ATAC 测序：结果：对死后人类基底前脑的测序分析确定了出生后早期DS的基因表达差异。编码与能量代谢途径（特别是氧化磷酸化和糖酵解）相关的蛋白质的基因以及编码抗氧化酶的基因在DS基底前脑中上调：讨论：多组学分析表明，DS BFCNs 的能量代谢可能在出生时就已被破坏。氧化磷酸化的增加和活性氧副产物的积累可能是导致DS BFCN神经变性的早期因素。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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bioRxiv : the preprint server for biology

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