LAUSR

Lysosomal storage diseases (LSD) are inherited metabolic diseases caused due to deficiency of lysosomal enzymes, essential for the normal development of the brain and other organs. Approximately two-thirds of the patients suffering from LSD exhibit neurological deficits and impose an escalating challenge to the medical and scientific field. The advent of iPSC technology has aided researchers in efficiently generating functional neuronal and non-neuronal cells through directed differentiation protocols, as well as in decoding the cellular, subcellular and molecular defects associated with LSDs using two-dimensional cultures and cerebral organoid models. This review highlights the information assembled from patient-derived iPSCs on neurodevelopmental and neuropathological defects identified in LSDs. Multiple studies have identified neural progenitor cell migration and differentiation defects, substrate accumulation, axon growth and myelination defects, impaired calcium homeostasis and altered electrophysiological properties, using patient-derived iPSCs. In addition, these studies have also uncovered defective lysosomes, mitochondria, endoplasmic reticulum, Golgi complex, autophagy and vesicle trafficking and signaling pathways, oxidative stress, neuroinflammation, blood brain barrier dysfunction, neurodegeneration, gliosis, altered transcriptomes in LSDs. The review also discusses the therapeutic applications such as drug discovery, repurposing of drugs, synergistic effects of drugs, targeted molecular therapies, gene therapy, and transplantation applications of mutation corrected lines identified using patient-derived iPSCs for different LSDs.