Vidyawan Vincencius, Puspita Lesly, Juwono Virginia Blessy, Deline Magdalena, Pieknell Kelvin, Chang Mi-Yoon, Lee Sang-Hun, Shim Jae-Won
Soonchunhyang Institute of Medi-Bio Science (SIMS), Soonchunhyang University, Cheonan-Si, Korea.
Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan-Si, Korea.
Autophagy. 2025 Apr;21(4):719-736. doi: 10.1080/15548627.2024.2407707. Epub 2024 Oct 9.
Macroautophagy/autophagy dysregulation is associated with various neurological diseases, including Vici syndrome. We aimed to determine the role of autophagy in early brain development. We generated neurons from human embryonic stem cells and developed a Vici syndrome model by introducing a loss-of-function mutation in the gene. Autophagy-related genes were upregulated at the neuronal progenitor cell stage. Inhibition of autolysosome formation with bafilomycin A treatment at the neuronal progenitor cell stage delayed neuronal differentiation. Notably, WNT (Wnt family member) signaling may be part of the underlying mechanism, which is negatively regulated by autophagy-mediated DVL2 (disheveled segment polarity protein 2) degradation. Disruption of autolysosome formation may lead to failure in the downregulation of WNT signaling, delaying neuronal differentiation. mutations disturbed autolysosome formation, subsequently inducing defects in progenitor cell differentiation and cortical layer generation in organoids. Disrupted autophagy leads to smaller organoids, recapitulating Vici syndrome-associated microcephaly, and validating the disease relevance of our study.: BafA1: bafilomycin A1; co-IP: co-immunoprecipitation; DVL2: dishevelled segment polarity protein 2; EPG5: ectopic P-granules 5 autophagy tethering factor; gRNA, guide RNA; hESC: human embryonic stem cells; KO: knockout; mDA, midbrain dopamine; NIM: neural induction media; NPC: neuronal progenitor cell; qPCR: quantitative polymerase chain reaction; UPS: ubiquitin-proteasome system; WNT: Wnt family member; WT: wild type.
巨自噬/自噬失调与包括维西综合征在内的多种神经疾病相关。我们旨在确定自噬在早期脑发育中的作用。我们从人类胚胎干细胞生成神经元，并通过在该基因中引入功能丧失突变建立了维西综合征模型。自噬相关基因在神经元祖细胞阶段上调。在神经元祖细胞阶段用巴佛洛霉素A处理抑制自溶酶体形成会延迟神经元分化。值得注意的是，WNT（Wnt家族成员）信号可能是潜在机制的一部分，该机制受到自噬介导的DVL2（散乱节段极性蛋白2）降解的负调控。自溶酶体形成的破坏可能导致WNT信号下调失败，从而延迟神经元分化。突变扰乱了自溶酶体形成，随后在类器官中诱导祖细胞分化和皮质层生成缺陷。自噬破坏导致类器官变小，重现了与维西综合征相关的小头畸形，并验证了我们研究与该疾病的相关性。：BafA1：巴佛洛霉素A1；co-IP：免疫共沉淀；DVL2：散乱节段极性蛋白2；EPG5：异位P颗粒5自噬栓系因子；gRNA，引导RNA；hESC：人类胚胎干细胞；KO：敲除；mDA，中脑多巴胺；NIM：神经诱导培养基；NPC：神经元祖细胞；qPCR：定量聚合酶链反应；UPS：泛素-蛋白酶体系统；WNT：Wnt家族成员；WT：野生型。
