Unbiased yeast screens identify cellular pathways affected in Niemann-Pick disease type C

Niemann-Pick disease type C (NPC) is a rare lysosomal storage disease caused by mutations in either the or genes. Mutations in the 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...

Full description

Saved in:
Bibliographic Details
Published in:Life science alliance 2020-07, Vol.3 (7), p.e201800253
Main Authors: Colaco, Alexandria, Fernández-Suárez, María E, Shepherd, Dawn, Gal, Lihi, Bibi, Chen, Chuartzman, Silvia, Diot, Alan, Morten, Karl, Eden, Emily, Porter, Forbes D, Poulton, Joanna, Platt, Nick, Schuldiner, Maya, Platt, Frances M
Format: Article
Language:English
Subjects:
Animals
Biomarkers
Carrier Proteins - metabolism
CHO Cells
Cricetulus
Cytoskeleton - metabolism
Disease Susceptibility
Fibroblasts - metabolism
Humans
Intracellular Membranes - metabolism
Intracellular Signaling Peptides and Proteins - genetics
Intracellular Signaling Peptides and Proteins - metabolism
Mitochondria - metabolism
Mutation
Niemann-Pick C1 Protein
Niemann-Pick Disease, Type C - diagnosis
Niemann-Pick Disease, Type C - etiology
Niemann-Pick Disease, Type C - metabolism
Protein Binding
Protein Interaction Mapping - methods
Protein Processing, Post-Translational
Protein Transport
Signal Transduction
Vacuoles - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Niemann-Pick disease type C (NPC) is a rare lysosomal storage disease caused by mutations in either the or genes. Mutations in the 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 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 -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 , confirming their dysfunction in NPC disease.
ISSN:2575-1077
2575-1077
DOI:10.26508/LSA.201800253