A Drosophila model of the Niemann-Pick type C lysosome storage disease: dnpc1a is required for molting and sterol homeostasis

Xun Huang,Alan J Zhu,Joann Buchanan,Kaye Suyama,Matthew P Scott

doi:10.1242/dev.02079

Xun Huang, Alan J Zhu + Show 3 more

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https://doi.org/10.1242/dev.02079

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Abstract

Niemann-Pick type C (NPC) disease is a fatal autosomal-recessive neurodegenerative disorder characterized by the inappropriate accumulation of unesterified cholesterol in aberrant organelles. The disease is due to mutations in either of two genes, NPC1, which encodes a transmembrane protein related to the Hedgehog receptor Patched, and NPC2, which encodes a secreted cholesterol-binding protein. Npc1 mutant mice can be partially rescued by treatment with specific steroids. We have created a Drosophila NPC model by mutating dnpc1a, one of two Drosophila genes related to mammalian NPC1. Cells throughout the bodies of dnpc1a mutants accumulated sterol in a punctate pattern, as in individuals with NPC1 mutations. The mutants developed only to the first larval stage and were unable to molt. Molting after the normal first instar period was restored to various degrees by feeding the mutants the steroid molting hormone 20-hydroxyecdysone, or the precursors of ecdysone biosynthesis, cholesterol and 7-dehydrocholesterol. dnpc1a is normally highly expressed in the ecdysone-producing ring gland. Ring gland-specific expression of dnpc1a in otherwise mutant flies allowed development to adulthood, suggesting that the lack of ecdysone in the mutants is the cause of death. We propose that dnpc1a mutants have sterols trapped in aberrant organelles, leading to a shortage of sterol in the endoplasmic reticulum and/or mitochondria of ring gland cells, and, consequently, inadequate ecdysone synthesis.

Highlights

Niemann-Pick Type C disease (NPC) is both a lysosomal storage disorder and a neurodegenerative disease
The results indicate that the enzymatic machinery for ecdysone biosynthesis is probably fine in dnpc1a mutants
As the Drosophila dnpc1a model recapitulates the sterol accumulation phenotypes of NPC disease, we investigated whether the flies have a neurodegeneration problem, another characteristic of mammalian NPC disease

Summary

Introduction

Niemann-Pick Type C disease (NPC) is both a lysosomal storage disorder and a neurodegenerative disease. The most notable aspect of the disease is a massive accumulation of cholesterol, glycosphingolipids and other lipids in aberrant organelles. The disease is caused by mutations in either of two genes, NPC1 (Carstea et al, 1997) and NPC2 (Naureckiene et al, 2000). Neurons in individuals with NPC gene mutations and in a cat model of the disease grow extra dendritic processes and form neurofibrillary tangles (NFTs) (Walkley and Suzuki, 2004), and progressive neurodegeneration is a prominent symptom, in the cerebellum (Higashi et al, 1993). Understanding the origins of NPC is important to find ways to save lives and because it provides an entry point for studying still-mysterious aspects of lipid and transport cell biology

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