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

• 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
• ISSN: 2575-1077; 2575-1077
• DOI: 10.26508/LSA.201800253

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.