Increased SNAI2 expression and defective collagen adhesion in cells with pediatric dementia, juvenile ceroid lipofuscinosis.

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 Ca chelator. These results provide new insights into the role of CLN3 and cell adhesion in the pathogenesis of NDD.