RT Journal Article
SR Electronic
T1 Unbiased yeast screens identify cellular pathways affected in Niemann–Pick disease type C
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e201800253
DO 10.26508/lsa.201800253
VO 3
IS 7
A1 Alexandria Colaco
A1 María E Fernández-Suárez
A1 Dawn Shepherd
A1 Lihi Gal
A1 Chen Bibi
A1 Silvia Chuartzman
A1 Alan Diot
A1 Karl Morten
A1 Emily Eden
A1 Forbes D Porter
A1 Joanna Poulton
A1 Nick Platt
A1 Maya Schuldiner
A1 Frances M Platt
YR 2020
UL https://www.life-science-alliance.org/content/3/7/e201800253.abstract
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.