PDF(Pubmed)
Abstract：
Phelan-McDermid syndrome (PMDS) arises from mutations in the terminal region of chromosome 22q13, impacting the SHANK3 gene. The resulting deficiency of the postsynaptic density scaffolding protein SHANK3 is associated with autism spectrum disorder (ASD). We examined 12 different PMDS patient and CRISPR-engineered stem cell-derived neuronal models and controls and found that reduced expression of SHANK3 leads to neuronal hyperdifferentiation, increased synapse formation, and decreased neuronal activity. We performed automated imaging-based screening of 7,120 target-annotated small molecules and identified three compounds that rescued SHANK3-dependent neuronal hyperdifferentiation. One compound, Benproperine, rescued the decreased colocalization of Actin Related Protein 2/3 Complex Subunit 2 (ARPC2) with ß-actin and rescued increased synapse formation in SHANK3 deficient neurons when administered early during differentiation. Neuronal activity was only mildly affected, highlighting Benproperine\'s effects as a neurodevelopmental modulator. This study demonstrates that small molecular compounds that reverse developmental phenotypes can be identified in human neuronal PMDS models.
摘要：
Phelan-McDermid综合征（PMDS）源于染色体22q13末端区域的突变，影响SHANK3基因。突触后密度支架蛋白SHANK3的缺乏与自闭症谱系障碍（ASD）有关。我们检查了12个不同的PMDS患者和CRISPR工程干细胞衍生的神经元模型和对照，发现SHANK3表达降低导致神经元过度分化。突触形成增加，神经元活动减少。我们对7,120个目标注释的小分子进行了基于自动成像的筛选，并鉴定了三种拯救SHANK3依赖性神经元过度分化的化合物。一种化合物，Benperine,在分化早期施用时,挽救了肌动蛋白相关蛋白2/3复合物亚基2(ARPC2)与β-肌动蛋白共定位的减少,并挽救了SHANK3缺陷神经元突触形成的增加。神经元活动只受到轻微影响，强调Benperiine作为神经发育调节剂的作用。这项研究表明，可以在人神经元PMDS模型中鉴定出逆转发育表型的小分子化合物。
