Abstract

Niemann Pick type C (NPC) disease is a rare neurovisceral disorder. Mutations in npc1 gene induce an intracellular accumulation of unesterified cholesterol in the endosomal/lysosomal system causing cell death. We recently showed that stimulation of adenosine A2A receptors (A2AR) restores cholesterol accumulation in late endosomes/lysosomes in human NPC fibroblasts and neural cell lines transiently transfected with NPC1 siRNA, suggesting that these receptors might be targeted to contrast the disease. Since NPC1 disease is characterized by dysmyelination and maturational arrest of oligodendrocyte progenitors (OPs), in this study, we investigated whether A2AR stimulation could promote oligodendrocyte differentiation and myelin formation, thus overcoming these important neurological abnormalities. We developed a NPC1 pharmacological model, in which primary cultures of OPs are exposed to a cholesterol transport inhibitor to induce a NPC1-like phenotype characterized by several typical features such as (i) cholesterol accumulation, (ii) altered mitochondrial morphology and membrane potential, (iii) defect of autophagy and (iv) maturation arrest. The A2AR agonist CGS21680 normalized all NPC1-like features. The ability of CGS21680 of rescuing OP from maturational arrest and promoting their differentiation to mature OL, suggests that A2AR stimulation might be exploited to correct dysmyelination in NPC1, further supporting their therapeutic potential in the disease.

Highlights

  • Niemann-Pick type C 1 disease (NPC1) is an autosomal recessive and progressive neurovisceral disorder

  • To assess whether U18666a induced an unbalance in autophagic flux, we considered three proteins involved in different stages of autophagy as Beclin 1, microtubule-associated protein 1 light chain 3 (LC3) and lysosome-associated membrane glycoprotein 2 (LAMP2)

  • We previously showed that the stimulation of A2A receptors (A2AR) is able to recover the abnormal phenotype of genetic Niemann Pick type C (NPC) models such as fibroblasts from NPC1 patients[15] and neuroblastoma SH-SY5Y and oligodendroglial MO3.13 cell lines transiently transfected with NPC1 siRNA16

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Summary

Introduction

Niemann-Pick type C 1 disease (NPC1) is an autosomal recessive and progressive neurovisceral disorder. We demonstrated that A2AR stimulation restores calcium homeostasis, mitochondrial membrane potential (mMP) and cholesterol accumulation in fibroblasts from NPC1 patients and in human neuronal and oligodendroglial NPC1 cell lines (i.e. neuroblastoma SH-SY5Y and oligodendroglial MO3.13) transiently transfected with NPC1 small interfering RNA15,16. These models were very useful to provide a clear in vitro proof of concept that A2AR agonists are promising potential drugs for NPC1 disease. Mean fluorescence intensities (MFI value) of Filipin III are shown in D.

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