痴呆相关的神经退行性疾病（NDD），包括阿尔茨海默病（AD），已知是由有毒蛋白质的积累引起的。然而，引起神经退行性变的分子机制及其对细胞的生物物理影响仍不清楚。在本研究中，我们使用幼年神经元蜡样脂褐质沉着症 (JNCL)（一种儿童痴呆症，其病因明确为蜡样质脂褐质沉着症神经元 3 (CLN3) 突变）来探索细胞粘附的变化，这是调节神经元发育和存活的生物物理过程。我们使用 JNCL 脑类器官基因表达数据集来识别影响神经发育的生物学通路，发现上皮间质转化（EMT）通路中的基因表达丰富，其诱导物 snail family 转录阻遏蛋白 2（SNAI2）的表达增加。使用 JNCL 患者的淋巴母细胞进行的细胞粘附测定显示，细胞培养板、玻璃表面、I 型胶原蛋白和神经母细胞样细胞的粘附有缺陷。为了确定抑制 EMT 是否可以改善 JNCL 淋巴母细胞的细胞粘附，我们使用了全反式视黄酸，这是一种众所周知的 EMT 抑制剂和神经分化诱导剂。在 JNCL 淋巴母细胞中，ATRA 治疗增强了对 I 型胶原蛋白的粘附，而这些作用被 Ca2 螯合剂消除。这些结果为 CLN3 和细胞粘附在 NDD 发病机制中的作用提供了新的见解。版权所有 © 2024 Elsevier Inc. 保留所有权利。

Dementia-related neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), are known to be caused by accumulation of toxic proteins. However, the molecular mechanisms that cause neurodegeneration and its biophysical effects on cells remain unclear. In this study, we used juvenile neuronal ceroid lipofuscinosis (JNCL), a pediatric dementia with a clear etiology of mutations in ceroid lipofuscinosis neuronal 3 (CLN3), to explore the changes in cell adhesion, a biophysical process that regulates neuronal development and survival. We used JNCL cerebral organoid gene expression datasets to identify the biological pathways that affect neural development, and found enriched gene expression in the epithelial-mesenchymal transition (EMT) pathway and increased expression of its inducer snail family transcriptional repressor 2 (SNAI2). A cell adhesion assay using lymphoblasts from patients with JNCL revealed defective adhesion to cell culture plates, glass surfaces, collagen type I, and neuroblast-like cells. To determine whether inhibition of EMT could improve the cell adhesion of JNCL lymphoblasts, we used all-trans retinoic acid, a well-known EMT inhibitor and inducer of neural differentiation. In JNCL lymphoblasts, ATRA treatment enhanced adhesion to collagen type I and these effects were abolished by Ca2+ chelator. These results provide new insights into the role of CLN3 and cell adhesion in the pathogenesis of NDD.Copyright © 2024 Elsevier Inc. All rights reserved.