Sex Differences in the Neuronal Transcriptome and Synaptic Mitochondrial Function in Cerebral Cortex of a Multiple Sclerosis Model. Sex Differences in the Neuronal Transcriptome and Synaptic Mitochondrial Function in Cerebral Cortex of a Multiple Sclerosis Model

Multiple sclerosis (MS) affects the cerebral cortex, inducing cortical atrophy and neuronal and synaptic pathology. Despite the fact that women are more susceptible to getting MS, men with MS have worse disability progression. Here, we address sex differences in neurodegenerative mechanisms focusing on the cerebral cortex using the MS model, chronic experimental autoimmune encephalomyelitis (EAE). RNA sequencing of neurons in cerebral cortex during EAE showed robust differential gene expression in male EAE mice compared to male healthy, age-matched, control mice. In contrast, there were few differences in female EAE mice compared to female controls. The most enriched differential gene expression pathways in male mice during EAE were mitochondrial dysfunction and oxidative phosphorylation. Mitochondrial morphology showed significant abnormalities in the cerebral cortex of EAE males, but not EAE females. Regarding function, synaptosomes isolated from cerebral cortex of male EAE mice demonstrated decreased oxygen consumption rates during respirometry assays. Together, cortical neuronal transcriptomics, mitochondrial morphology, and functional respirometry assays in synaptosomes revealed worse neurodegeneration in male EAE mice. This is consistent with worse neurodegeneration in MS men and reveals a model and a target to develop treatments to prevent cortical neurodegeneration and mitigate disability progression in MS men. Overall design: Comparative gene expression profiling analysis of RNA-seq data for cortex neuron RNAs

多发性硬化症（Multiple Sclerosis, MS）可侵袭大脑皮层，引发皮层萎缩及神经元与突触病变。尽管女性群体更易罹患MS，但男性MS患者的残疾进展更为严峻。本研究以MS模型——慢性实验性自身免疫性脑脊髓炎（chronic experimental autoimmune encephalomyelitis, EAE）为研究载体，聚焦大脑皮层探讨神经退行性机制中的性别差异。我们对EAE模型小鼠大脑皮层的神经元进行RNA测序（RNA sequencing）分析，结果显示，与同龄健康雄性对照小鼠相比，雄性EAE小鼠存在显著的差异基因表达；与之形成鲜明对比的是，雌性EAE小鼠与雌性对照小鼠间的差异基因表达极为有限。雄性EAE小鼠中富集度最高的差异基因表达通路为线粒体功能异常与氧化磷酸化。雄性EAE小鼠大脑皮层的线粒体形态出现显著异常，而雌性EAE小鼠则未观察到此类改变。在功能层面，从雄性EAE小鼠大脑皮层分离的突触小体在呼吸测定实验中呈现出耗氧速率降低的表现。综上，皮层神经元转录组学分析、线粒体形态学观察以及突触小体呼吸测定实验的结果均表明，雄性EAE小鼠的神经退行性变更为严重。这一发现与男性MS患者更显著的神经退行性变表现相一致，同时为开发针对男性MS患者的皮层神经退行性变预防手段、减缓其残疾进展提供了实验模型与潜在治疗靶点。整体实验设计：对皮层神经元RNA的RNA测序数据进行比较基因表达谱分析。