Abstract

Niemann-Pick Type C Disease: At the Nexus of Neurodegenerative and Neurodevelopmental Disorders

Highlights

  • Neurodevelopmental and neurodegenerative diseases are generally thought to differ fundamentally in cause, course of disease and disease phenotype

  • NPC1 forms a complex with the lysosomal transmembrane protein SLC38A9 which mediates cholesterol activation of mammalian target of rapamycin (mTOR) complex 1 [61]. mTORC1 regulates sterol regulatory element binding proteins (SREBP)1 and SREBP2 activity [62,63]. mTOR is a link between Alzheimer’s Disease (AD), in which mTOR is chronically activated with detrimental impact on autophagy and tau phosphorylation [6466], and schizophrenia which is characterized by hypofunction of the mTOR pathway [67]

  • Niemann-Pick disease type C (NPC) is a lysosomal storage disease, a category of neurodegenerative disorders that includes the sphingolipidoses. This class of disorders is characterized by aberrations in sphingolipid metabolism and includes Niemann-Pick disease types A and B caused by defects in sphingomyelinase (SMPD1), Gaucher’s disease caused by galactosidase (GBA1) deficiency, Fabry’s disease associated with α- galactosidase-A (GLA) deficiency, Krabbe disease associated with galactosidase (GALC) deficiency, Tay-Sachs caused by β-hexosaminidase-A mutations and metachromatic leukodystrophy (MLD) resulting from defects in arylsulfatase A (ARSA) [121]

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Summary

Inviting Innovations

Rare genetic diseases can provide valuable insights into more common disorders by linking specific genes and pathways to shared disease phenotypes. The rare Niemann-Pick Type C disease (NPC) is a neurological disorder that has often been compared to Alzheimer’s Disease (AD) because both diseases are characterized by cognitive impairment in the presence of tau pathology and altered Amyloid Precursor Protein (APP) processing and Aβ metabolism. Besides the phenotypic overlap between AD and NPC, there is substantial evidence that cholesterol metabolism is altered in both diseases. In addition to features that are in common with AD, NPC frequently exhibits close phenotypic overlap with neurodevelopmental disorders such as schizophrenia. Understanding the mechanistic links shared by NPC, AD, and neurodevelopmental disorders should enable a more holistic approach to therapeutic strategies to diseases which superficially appear very different. Infantile and juvenile forms of NPC present with anatomical abnormalities in the liver, spleen

Introduction
Behavioural Pathology Lipid Metabolism
Lewy Bodies
Elevated free fatty
Human Studies
Mouse Models
NPC Proteins as pharmacological targets
Current treatment strategies
NPC and other neurodegenerative diseases
NPC and other neurodevelopmental disorders
Findings
Discussion and Conclusion
Full Text
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