Lysosomal free sialic acid storage disorder iPSC-derived neural cells display altered glycosphingolipid metabolism

Lysosomal free sialic acid storage disorder (FSASD) is a rare neurodegenerative disease caused by biallelic mutations in SLC17A5, encoding the lysosomal sialic acid exporter, SLC17A5 (sialin). While the involvement of oligodendroglia in FSASD pathogenesis is established, the roles of other neural cell types remain elusive. In this study, we utilized radial glial cells (iRGCs), immature and mature astrocytes (iIAs and iMAs, respectively), and cortical neurons (iCNs) differentiated from induced pluripotent stem cells (iPSCs) derived from two individuals with FSASD, alongside two independent healthy donors for comparison. We employed a multifaceted profiling approach, including the assessment of cellular glycosphingolipids (GSLs), transcriptomics focused on GSL metabolism genes, and 4-methylumbelliferone-based lysosomal enzyme activity measurements. Our findings revealed significant elevations in free sialic acid levels across all FSASD cell types, indicating that iPSCs and derived iRGCs, iIAs, iMAs and iCNs may be used to model FSASD in vitro. We observed significant alterations in the abundance of specific GSL species, predominantly in mature astrocytes, with fewer changes in other cell types. Transcriptomic analyses uncovered differential expression of genes involved in GSL catabolism, including those encoding glycohydrolases. Enzyme assays corroborated the transcriptomic findings, showing heightened glycohydrolase activities, particularly in mature astrocytes. Collectively, these data may help refine our understanding of neural cell phenotypes and potential contributors to selective vulnerability in FSASD.