Neural stem cells as model to study neurodegeneration and novel therapeutics in lysosomal storage disorders

Abstract

Neural Stem Cells (NSCs) are self-renewing multipotent populations responsible for the generation of neurons and glial cells of the developing brain and account for the limited regenerative plasticity of the adult brain. In view of their reliable use as cellular model to study neurodegenerative diseases, and as potential donors in cell-based therapeutic approaches, we have isolated and characterized NSCs from a mouse model of a neurodegenerative Lysosomal Storage Disorder (LSD), the Multiple Sulfatase Deficiency (MSD), caused by mutations in the sulfatase modifying factor 1 (SUMF1) gene that encodes the enzyme responsible for sulfatase activation. Isolated MSD-NSCs are phenotypically similar to wild-type precursors and are able to differentiate into neurons and astrocytes, although they show a progressive loss of their self-renewal capacity. Moreover, differentiated MSD cells recapitulate the main pathological features of the disease, such as progressive cell vacuolization, lysosomal accumulation of glycosaminoglycans (GAGs), altered autophagy with accumulation of poly-ubiquitinated proteins, and increased levels of apoptosis. Interestingly, glia-differentiated MSD cells display the tendency to form aggresomes, perinuclear aggregates of misfolded protein, which is a common feature to many neurodegenerative diseases. We also showed that the overexpression of the Transcription Factor EB (TFEB), a master-gene that modulate lysosomal function and autophagy, induces lysosomal exocytosis through activation of mucolipin 1 (MCOLN1) and reduces significantly primary and secondary pathologic storage, ameliorating the phenotype of MSD cells (Medina et al. 2011). These results validate the use of NSCs isolated from LSD mouse models to study their neurodegenerative phenotype, and envisage their use to explore new therapeutic approaches by the modulation of TFEB expression in LSDs.