Abstract
Niemann-Pick disease type C (NPC) is a rare lysosomal storage disease caused by mutations in either the NPC1 or NPC2 genes. Mutations in the NPC1 gene lead to the majority of clinical cases (95%); however, the function of NPC1 remains unknown. To gain further insights into the biology of NPC1, we took advantage of the homology between the human NPC1 protein and its yeast orthologue, Niemann-Pick C-related protein 1 (Ncr1). We recreated the NCR1 mutant in yeast and performed screens to identify compensatory or redundant pathways that may be involved in NPC pathology, as well as proteins that were mislocalized in NCR1-deficient yeast. We also identified binding partners of the yeast Ncr1 orthologue. These screens identified several processes and pathways that may contribute to NPC pathogenesis. These included alterations in mitochondrial function, cytoskeleton organization, metal ion homeostasis, lipid trafficking, calcium signalling, and nutrient sensing. The mitochondrial and cytoskeletal abnormalities were validated in patient cells carrying mutations in NPC1, confirming their dysfunction in NPC disease.
Highlights
Niemann–Pick disease type C (NPC) is an autosomal recessive lysosomal storage disorder characterized by progressive neurodegeneration
Because only vacuolar membrane proteins were used in the screen, known interactors such as Npc2, which resides in the vacuole lumen, were not observed
We have investigated novel aspects of the cellular features of NPC disease by taking advantage of the highly conserved yeast Niemann–Pick C–related protein 1 (Ncr1) protein orthologue of NPC1
Summary
Niemann–Pick disease type C (NPC) is an autosomal recessive lysosomal storage disorder characterized by progressive neurodegeneration. NPC is caused by mutations in either the NPC1 or NPC2 genes, resulting in identical clinical phenotypes irrespective of which gene is affected [1]. Mutations in NPC1 account for the majority of observed clinical cases (95%); the exact function of this protein remains incompletely understood. NPC1 is a 13 transmembrane domain protein that contains a sterol-sensing domain and has structural similarities with resistance-nodulationdivision permeases (multi-substrate effluxors) [4, 5]. The highly conserved structure of the NPC1 protein makes it a good target for studies in simpler model eukaryotes that may provide novel insights into its conserved functions
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