近日，美国加州大学洛杉矶分校Daniel H. Geschwind等研究人员合作发现，ASD的整个大脑皮层出现广泛的转录组失调。该项研究成果于2022年11月2日在线发表在《自然》杂志上。

研究人员表示，神经精神障碍通常缺乏明确的脑部病理，但最近的工作表明，在分子水平上的调节失调，其特点是转录组和表观遗传学的改变。在自闭症谱系障碍（ASD）中，这种分子病理学涉及小胶质细胞、星形细胞和神经免疫基因的上调，突触基因的下调，以及皮层中基因表达梯度的衰减。然而，这些变化是否仅限于皮层关联区域或更广泛，仍然是未知的。

为了解决这个问题，研究人员对112个来自ASD患者和神经正常对照者的死后样本中横跨11个皮层区域的725个大脑样本进行了RNA测序分析。研究人员发现在ASD中整个皮层广泛的转录组变化，表现为从前到后的梯度，其中初级视觉皮层的差异最大，与皮层区域之间典型的转录组差异的衰减相吻合。单核RNA测序和甲基化分析表明，这种强大的分子特征反映了细胞类型特异性基因表达的变化，特别是影响兴奋性神经元和胶质细胞。罕见和常见的ASD相关遗传变异都汇聚在涉及突触信号的下调共表达模块中，而仅常见的变异则富集在上调的蛋白伴侣基因模块中。

这些结果突出了ASD中整个大脑皮层广泛的分子变化，超出了联合皮层的范围，广泛涉及初级感觉区域。

附：英文原文

Title: Broad transcriptomic dysregulation occurs across the cerebral cortex in ASD

Author: Gandal, Michael J., Haney, Jillian R., Wamsley, Brie, Yap, Chloe X., Parhami, Sepideh, Emani, Prashant S., Chang, Nathan, Chen, George T., Hoftman, Gil D., de Alba, Diego, Ramaswami, Gokul, Hartl, Christopher L., Bhattacharya, Arjun, Luo, Chongyuan, Jin, Ting, Wang, Daifeng, Kawaguchi, Riki, Quintero, Diana, Ou, Jing, Wu, Ye Emily, Parikshak, Neelroop N., Swarup, Vivek, Belgard, T. Grant, Gerstein, Mark, Pasaniuc, Bogdan, Geschwind, Daniel H.

Issue&Volume: 2022-11-02

Abstract: Neuropsychiatric disorders classically lack defining brain pathologies, but recent work has demonstrated dysregulation at the molecular level, characterized by transcriptomic and epigenetic alterations1,2,3. In autism spectrum disorder (ASD), this molecular pathology involves the upregulation of microglial, astrocyte and neural–immune genes, the downregulation of synaptic genes, and attenuation of gene-expression gradients in cortex1,2,4,5,6. However, whether these changes are limited to cortical association regions or are more widespread remains unknown. To address this issue, we performed RNA-sequencing analysis of 725 brain samples spanning 11 cortical areas from 112 post-mortem samples from individuals with ASD and neurotypical controls. We find widespread transcriptomic changes across the cortex in ASD, exhibiting an anterior-to-posterior gradient, with the greatest differences in primary visual cortex, coincident with an attenuation of the typical transcriptomic differences between cortical regions. Single-nucleus RNA-sequencing and methylation profiling demonstrate that this robust molecular signature reflects changes in cell-type-specific gene expression, particularly affecting excitatory neurons and glia. Both rare and common ASD-associated genetic variation converge within a downregulated co-expression module involving synaptic signalling, and common variation alone is enriched within a module of upregulated protein chaperone genes. These results highlight widespread molecular changes across the cerebral cortex in ASD, extending beyond association cortex to broadly involve primary sensory regions.

DOI: 10.1038/s41586-022-05377-7

Source: https://www.nature.com/articles/s41586-022-05377-7