PT  - JOURNAL ARTICLE
AU  - Colaco, Alexandria
AU  - Fernández-Suárez, María E
AU  - Shepherd, Dawn
AU  - Gal, Lihi
AU  - Bibi, Chen
AU  - Chuartzman, Silvia
AU  - Diot, Alan
AU  - Morten, Karl
AU  - Eden, Emily
AU  - Porter, Forbes D
AU  - Poulton, Joanna
AU  - Platt, Nick
AU  - Schuldiner, Maya
AU  - Platt, Frances M
TI  - Unbiased yeast screens identify cellular pathways affected in Niemann–Pick disease type C
AID  - 10.26508/lsa.201800253
DP  - 2020 Jul 01
TA  - Life Science Alliance
PG  - e201800253
VI  - 3
IP  - 7
4099  - https://www.life-science-alliance.org/content/3/7/e201800253.short
4100  - https://www.life-science-alliance.org/content/3/7/e201800253.full
SO  - Life Sci. Alliance2020 Jul 01; 3
AB  - 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.