Abstract
Niemann–Pick disease type C (NPC) is a recessive hereditary disease caused by mutation of the NPC1 or NPC2 gene. It is characterized by abnormality of cellular cholesterol trafficking with severe neuronal and hepatic injury. In this study, we investigated the potential of glycoprotein nonmetastatic melanoma protein B (GPNMB) to act as a biomarker reflecting the therapeutic effect of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) in an NPC mouse model. We measured serum, brain, and liver expression levels of GPNMB, and evaluated their therapeutic effects on NPC manifestations in the brain and liver after the intracerebroventricular administration of HP-β-CD in Npc1 gene-deficient (Npc1−/−) mice. Intracerebroventricular HP-β-CD inhibited cerebellar Purkinje cell damage in Npc1−/− mice and significantly reduced serum and cerebellar GPNMB levels. Interestingly, we also observed that the intracerebral administration significantly reduced hepatic GPNMB expression and elevated serum ALT in Npc1−/− mice. Repeated doses of intracerebroventricular HP-β-CD (30 mg/kg, started at 4 weeks of age and repeated every 2 weeks) drastically extended the lifespan of Npc1−/− mice compared with saline treatment. In summary, our results suggest that GPNMB level in serum is a potential biomarker for evaluating the attenuation of NPC pathophysiology by intracerebroventricular HP-β-CD treatment.
Highlights
Niemann–Pick disease type C (NPC) is an autosomal recessive disorder that develops as a result of NPC1 or NPC2 gene mutation (95% and 5% of patients, respectively) and has been identified as a severe disease associated with lysosomal dysfunction [1]
To confirm the potential of HP-β-CD administered intracerebroventricularly to attenuate the neurological deficits in the cerebellum, calbindin immunostaining was performed in Npc1−/− mice [14,15]
In the saline-treated Npc1−/− mouse group, few calbindin-positive cells were found compared with the level in the saline-treated wildtype group in the observation conducted at 8 weeks of age
Summary
Niemann–Pick disease type C (NPC) is an autosomal recessive disorder that develops as a result of NPC1 or NPC2 gene mutation (95% and 5% of patients, respectively) and has been identified as a severe disease associated with lysosomal dysfunction [1]. NPC1/2 protein dysfunction leads to the accumulation of free cholesterol and depletion of esterified cholesterol in cells throughout the body of model animals and patients [2,3]. Animals and patients with NPC experience systemic symptoms, including neurological dysfunction and severe liver dysfunction [4]. The symptoms of NPC, neurological dysfunction, progressively worsen in most patients, so there is an urgent need to develop an effective cure. Some studies have indicated that HP-β-CD has potential benefits against manifestations of NPC in cellular and animal models [5,6,7]
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