Abstract
The lysosomal storage disorders Niemann-Pick disease Type C1 (NPC1) and Type C2 (NPC2) are rare diseases caused by mutations in the NPC1 or NPC2 gene. Both NPC1 and NPC2 are proteins responsible for the exit of cholesterol from late endosomes and lysosomes (LE/LY). Consequently, mutations in one of the two proteins lead to the accumulation of unesterified cholesterol and glycosphingolipids in LE/LY, displaying a disease hallmark. A total of 95% of cases are due to a deficiency of NPC1 and only 5% are caused by NPC2 deficiency. Clinical manifestations include neurological symptoms and systemic symptoms, such as hepatosplenomegaly and pulmonary manifestations, the latter being particularly pronounced in NPC2 patients. NPC1 and NPC2 are rare diseases with the described neurovisceral clinical picture, but studies with human primary patient-derived neurons and hepatocytes are hardly feasible. Obviously, induced pluripotent stem cells (iPSCs) and their derivatives are an excellent alternative for indispensable studies with these affected cell types to study the multisystemic disease NPC1. Here, we present a review focusing on studies that have used iPSCs for disease modeling and drug discovery in NPC1 and draw a comparison to commonly used NPC1 models.
Highlights
Niemann-Pick disease type C is a rare monogenic neurovisceral lysosomal storage disorder, inherited in an autosomal recessive manner, with an estimated incidence of1/120,000 [1]
This study proved that Niemann-Pick disease Type C1 (NPC1) patient-specific induced pluripotent stem cells (iPSCs) can be differentiated into functional neurons, which was shown by the expression of voltage-activated and ligand-activated ion channels
We summarize studies that involve the use of patientderived iPSCs, and studies that use other NPC1 models, such as patients’ fibroblasts or murine models
Summary
Niemann-Pick disease type C is a rare monogenic neurovisceral lysosomal storage disorder, inherited in an autosomal recessive manner, with an estimated incidence of. Patients with the late infantile form (2–6 years) lose already acquired motor skills, resulting in frequent falling and clumsiness They show progressive ataxia, dystonia, dysphagia, and dysarthria. Research using iPSC-based model systems is progressing rapidly, and we want to recapitulate the current status of iPSC-based model systems used to study the pathomechanisms of Niemann-Pick type C1 disease. To this end, we will travel from standard NPC1 models to the exciting field of pluripotent stem cells and discuss their application in disease modeling and drug discovery for NPC1
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