Fatemi S Hossein, Folsom Timothy D, Eschenlauer Arthur, Chekouo Thierry
Department of Psychiatry and Behavioral Sciences, University of Minnesota Medical School, 420 Delaware Street SE, Minneapolis, MN, 55455, USA.
Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, 55455, USA.
Cerebellum. 2025 Aug 8;24(5):140. doi: 10.1007/s12311-025-01880-5.
Autism spectrum disorder (ASD) is a debilitating neurodevelopmental disorder with genetic and environmental etiologies involving several brain areas exhibiting abnormalities of cognition and social behavior. Previous work showed involvement of synaptic abnormalities in dorsolateral prefrontal cortex [1]. We hypothesized whether similar synaptic proteins were involved in pathology of cerebellar vermis of children and adults with ASD. Subcellular fractions of synaptosomes from cerebellar vermal cortices of age-, brain area-, and postmortem-interval-matched samples from children and adults with idiopathic ASD vs. controls were subjected to HPLC-tandem mass spectrometry. Analysis of proteomic data in cerebellar vermis of children with ASD showed enrichment of significantly downregulated pathways and proteins (FDR-adjusted < 0.05) involved in protein folding, Rho GTPase cycle, aggrephagy, macroautophagy, anterograde and retrograde transport, proteinopathy, protein stability, and cell response to stress. Enrichment of significantly upregulated pathways and proteins (FDR-adjusted < 0.05) involved processes of glycolysis, gluconeogenesis, metabolism of amino acids, and degradation of lysine, fatty acids, valine, leucine, and isoleucine. Analysis of proteomic data in cerebellar vermis of adults with ASD showed enrichment of significantly downregulated pathways and proteins (FDR-adjusted < 0.05) involved in aggrephagy, COPI-mediated anterograde transport and COPI-independent Golgi-to-ER retrograde transport, endocytosis, presynaptic, postsynaptic, and PSD related vesicle mediated activities, serotonin and dopamine neurotransmitter release, and neurodegeneration-related diseases. Enrichment of significantly upregulated pathways and proteins (FDR-adjusted < 0.05) in adults with ASD included peptide cross-linking, amyloidosis, intermediate filament organization, citrullination, methylation, and proteolysis. Overall, the proteomic data support the concept that cerebellar abnormalities in synaptic structure and function begin during fetal cerebellar development [2], culminate in early childhood, and evolve into adulthood, consistent with pathologic involvement of genes subserving the cognitive domains in ASD.
The online version contains supplementary material available at 10.1007/s12311-025-01880-5.
自闭症谱系障碍（ASD）是一种使人衰弱的神经发育障碍，其遗传和环境病因涉及多个脑区，这些脑区表现出认知和社会行为异常。先前的研究表明背外侧前额叶皮质存在突触异常[1]。我们推测是否有类似的突触蛋白参与患有ASD的儿童和成人小脑蚓部的病理过程。对来自患有特发性ASD的儿童和成人与对照组的年龄、脑区和死后间隔匹配样本的小脑蚓部皮质突触体的亚细胞组分进行了高效液相色谱-串联质谱分析。对患有ASD的儿童小脑蚓部的蛋白质组学数据分析显示，参与蛋白质折叠、Rho GTP酶循环、聚集体自噬、巨自噬、顺行和逆行转运、蛋白病、蛋白质稳定性以及细胞应激反应的显著下调途径和蛋白质（FDR校正<0.05）富集。显著上调途径和蛋白质（FDR校正<0.05）的富集涉及糖酵解、糖异生、氨基酸代谢以及赖氨酸、脂肪酸、缬氨酸、亮氨酸和异亮氨酸的降解过程。对患有ASD的成人小脑蚓部的蛋白质组学数据分析显示，参与聚集体自噬、COPI介导的顺行转运和不依赖COPI的高尔基体到内质网逆行转运、内吞作用、突触前、突触后和与突触后致密部相关的囊泡介导活动、5-羟色胺和多巴胺神经递质释放以及神经退行性疾病相关途径和蛋白质显著下调（FDR校正<0.05）。患有ASD的成人中显著上调途径和蛋白质（FDR校正<0.05）的富集包括肽交联、淀粉样变性、中间丝组织、瓜氨酸化、甲基化和蛋白水解。总体而言，蛋白质组学数据支持这样的概念，即突触结构和功能的小脑异常始于胎儿期小脑发育[2]，在幼儿期达到顶峰，并发展至成年期，这与ASD中服务于认知领域的基因的病理参与一致。
在线版本包含可在10.1007/s12311-025-01880-5获取的补充材料。
