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Patient iPSC-derived neural stem cells display progressive enlargement of lysosomes and disruptions of glycosaminoglycan pathway and autophagy in concordance with clinical severity of Mucopolysaccharidosis I

ABSTRACT: Mucopolysaccharidosis type I (MPS I) is caused by genetic defects in alpha-L-iduronidase (IDUA), a lysosomal enzyme involved in the breakdown and recycling of glycosaminoglycans (GAGs). Although an enzyme replacement therapy is available, the efficacy for the treatment of neuropathic symptoms is limited. To facilitate drug discovery and model disease pathophysiology, we have generated neural stem cells (NSCs) from MPS I patient-derived iPSCs. NSCs exhibited characteristic disease phenotypes with deficiency of alpha-L-iduronidase (IDUA), accumulation of glycosaminoglycans (GAGs) and enlargement of lysosomes, correlating with the severity of clinical symptoms. Transcriptome profiling of NSCs revealed differential expression of 429 genes that changed more extensively in the more severe Hurler syndrome subgroup compared to the Hurler-Scheie (median severe) and Scheie (less severe) subgroups. Clustering and pathway analyses demonstrated high concordance of the severity of neurological defects with marked dysregulation of GAG biosynthesis and degradation, lysosomal function and extracellular matrix. Gene Ontology (GO) analysis identified a dramatic upregulation of autophagy pathway, especially in the Hurler syndrome. Thus, GAG accumulation in the patient cells disrupts lysosomal homeostasis affecting multiple related cellular pathways which compensates for IDUA deficiency. These dysregulated process likely lead to enhanced autophagy and more severe disease states. Our studies provide useful tools for clinical biomarker development and potential targets for drug development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE111906 | GEO | 2018/10/18

REPOSITORIES: GEO

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Project description:Cutaneous lupus erythematosus (CLE) is an autoimmune disease that localizes to the skin and is known to contain elevated glycosaminoglycans (GAGs) on Hale’s stain of skin biopsy specimens. Recently, different GAG species have been shown to have distinct effects on the recruitment and activation of immune cells and stimulation of cytokine production (Taylor and Gallo, FASEB, 2006; 20: 9-22). Thus, we speculate that the elevated GAGs observed in CLE play a role in the local inflammatory process that produces skin lesions in these patients. In order to further investigate a molecular basis for the elevated expression of these GAGs in CLE skin lesions, we would like to determine the gene expression profiles of GAG synthesis, degradation, and modifier genes in lesional and non-lesional skin samples from CLE patients and compare to those from healthy controls. A microarray approach will give us a broader understanding of the genetic regulation of the expression of various GAG species in CLE skin. We will then be able to target future quantitative gene expression experiments by real-time RT-PCR to the genes that are shown to be involved in CLE. In order to accomplish our goal, we would like to examine the GAG gene expression profiles of DLE, TLE, and SCLE subtypes due to the differences in CS and HA staining that we found among these subtypes. Since HA and CS are elevated in DLE and HA in TLE, but not in SCLE, the SCLE samples will also serve as an internal control. We would like to examine both lesional and non-lesional skin biopsies to determine if CLE skin prior to developing a lesion is different at the genetic level from healthy control skin and how it changes once a lesion does develop. We will separate the dermis from the epidermis of the skin biopsies and extract RNA just from the dermis to enrich for dermal fibroblast RNA. We aim to submit four patient biopsies per subtype as well as four samples from healthy control skin for comparison. This number is necessary in order to account for the biologic variability among different patients. We would submit more samples per subtype but are limited by availability of patients in clinic. Thus, we will have a total of 28 samples to submit for microarray. This study design will allow us to analyze the GAG gene expression profiles among different CLE subtypes and enable us to identify which GAc

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Patient iPSC-derived neural stem cells display progressive enlargement of lysosomes and disruptions of glycosaminoglycan pathway and autophagy in concordance with clinical severity of Mucopolysaccharidosis I

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