Loss of Inpp5d has disease-relevant and sex-specific effects on glial transcriptomes

INTRODUCTION: INPP5D is genetically associated with Alzheimers disease risk. Loss of Inpp5d alters amyloid pathology in models of amyloidosis. Inpp5d is predominantly expressed in microglia but its function in brain is poorly understood. METHODS: We performed single-cell RNA-sequencing to study the effect of Inpp5d loss on wild-type mouse brain transcriptomes. RESULTS: Loss of Inpp5d has sex-specific effects on the brain transcriptome. Affected genes are enriched for multiple neurodegeneration terms. Network analyses reveal a gene co-expression module centered around Inpp5d in female mice. Inpp5d loss alters PTN, PSAP, and VEGFA signaling probability between cell types. DISCUSSION: Our data suggest Inpp5ds normal function is entangled with mechanisms involved in neurodegeneration. We report the effect of Inpp5d loss without pathology and show that this has dramatic effects on gene expression. Our study provides a critical reference for researchers of neurodegeneration, allowing separation of disease-specific changes mediated by Inpp5d in disease from baseline effects of Inpp5d loss. Data contains single-cell RNA-sequencing data from two female and male wildtype, two female and male Inpp5d hetereozygous knockout, two female and male Inpp5d homozygous knockout mice, all six weeks of age.研究背景：肌醇多磷酸-5-磷酸酶D（INPP5D）与阿尔茨海默病（Alzheimer's disease, AD）的遗传风险存在关联。Inpp5d基因缺失可改变淀粉样变性模型中的淀粉样蛋白病理进程。Inpp5d主要在小胶质细胞（microglia）中表达，但目前对其在大脑内的功能尚缺乏深入了解。 研究方法：本研究采用单细胞RNA测序（single-cell RNA-sequencing）技术，探究Inpp5d基因缺失对野生型小鼠大脑转录组的影响。 研究结果：Inpp5d基因缺失对大脑转录组的调控作用存在性别特异性。受其影响的基因富集于多个神经退行性疾病相关功能条目。共表达网络分析显示，雌性小鼠体内存在一个以Inpp5d为核心的基因共表达模块。Inpp5d基因缺失会改变不同细胞类型间多效生长因子（PTN）、脑苷脂激活蛋白（PSAP）及血管内皮生长因子A（VEGFA）的信号交互概率。 讨论：本研究数据表明，Inpp5d的正常功能与神经退行性疾病相关机制紧密关联。本研究首次报道了无病理状态下Inpp5d基因缺失的生物学效应，并证实其对基因表达具有显著调控作用。本研究为神经退行性疾病领域的研究者提供了关键参考依据，可用于区分疾病状态下由Inpp5d介导的疾病特异性变化与Inpp5d基因缺失的基线效应。本数据集包含6周龄小鼠的单细胞RNA测序数据，涵盖雌雄野生型小鼠、雌雄Inpp5d杂合敲除小鼠及雌雄Inpp5d纯合敲除小鼠各2例。