Prader-Willi Syndrome (PWS) is a rare neurodevelopmental disorder of genetic etiology, characterized by paternal deletion of genes located at chromosome 15 in 70% of cases. Two distinct genetic subtypes of PWS deletions are characterized, where type I (PWS T1) carries four extra haploinsufficient genes compared to type II (PWS T2). PWS T1 individuals display more pronounced physiological and cognitive abnormalities than PWS T2, yet the exact neuropathological mechanisms behind these differences remain unclear. Our study employed postmortem hypothalamic tissues from PWS T1 and T2 individuals, conducting transcriptomic analyses and cell-specific protein profiling in white matter, neurons, and glial cells to unravel the cellular and molecular basis of phenotypic severity in PWS sub-genotypes. In PWS T1, key pathways for cell structure, integrity, and neuronal communication are notably diminished, while glymphatic system activity is heightened compared to PWS T2. The microglial defect in PWS T1 appears to stem from gene haploinsufficiency, as global and myeloid-specific Cyfip1 haploinsufficiency in murine models demonstrated. Our findings emphasize microglial phagolysosome dysfunction and altered neural communication as crucial contributors to the severity of PWS T1’s phenotype.

普瑞德-威利综合征 (PWS) 是一种罕见的遗传性神经发育障碍，其特征是 70% 的病例存在父系 15 号染色体基因缺失。 PWS 缺失有两种不同的遗传亚型，其中 I 型 (PWS T1) 与 II 型 (PWS T2) 相比携带四个额外的单倍体不足基因。 PWS T1 个体比 PWS T2 个体表现出更明显的生理和认知异常，但这些差异背后的确切神经病理机制仍不清楚。我们的研究采用 PWS T1 和 T2 个体的死后下丘脑组织，对白质、神经元和神经胶质细胞进行转录组分析和细胞特异性蛋白质分析，以揭示 PWS 亚基因型表型严重程度的细胞和分子基础。与 PWS T2 相比，在 PWS T1 中，细胞结构、完整性和神经元通讯的关键通路显着减少，而类淋巴系统活动则增强。 PWS T1 中的小胶质细胞缺陷似乎源于基因单倍体不足，正如小鼠模型中整体和骨髓特异性Cyfip1单倍体不足所证明的那样。我们的研究结果强调小胶质细胞吞噬溶酶体功能障碍和神经通讯改变是 PWS T1 表型严重程度的关键因素。