Niemann-Pick type C disease: cellular pathology and pharmacotherapy

Date

2019-10-14

Advisors

Journal Title

Journal ISSN

ISSN

1471-4159

Volume Title

Publisher

Wiley

Type

Article

Peer reviewed

Yes

Abstract

Niemann-Pick type C disease (NPCD) was first described in 1914 and affects approximately 1 in 150,000 live births. It is characterised clinically by diverse symptoms affecting liver, spleen, motor control and brain; premature death invariably results.Its molecular originswere traced, as late as 1997, to a protein of late endosomes and lysosomes which was named NPC1. Mutation or absence of this protein leads to accumulation of cholesterol in these organelles. In this review we focus on the intracellular events that drive the pathology of this disease. We first introduce endocytosis, a much-studied area of dysfunction in NPCD cells, and survey the various ways in which this process malfunctions. We briefly consider autophagy before attempting to map the more complex pathways by which lysosomal cholesterol storage leads to protein misregulation, mitochondrial dysfunction and cell death. We then briefly introduce the metabolic pathways of sphingolipids (as these emerge as key species for treatment) and critically examine the various treatment approaches that have been attempted to date.

Description

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.

Keywords

Niemann–Pick, lipids, NPC1, GBA2, Glycolipids, Gaucher, endolysosome

Citation

Wheeler, S., Sillence, D.J. (2019) Niemann-Pick type C disease: cellular pathology and pharmacotherapy. Journal of Neurochemistry,

Rights

Research Institute

Leicester Institute for Pharmaceutical Innovation - From Molecules to Practice (LIPI)