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

Alexandria Colaco, Maria E. Fernandez-Suarez, Dawn Shepherd, Lihi Gal, Chen Bibi, Silvia Chuartzman, Alan Diot, Karl Morten, Emily Eden, Forbes D. Porter, Joanna Poulton, Nick Platt, Maya Schuldiner, Frances M. Platt

Research output: Contribution to journalArticlepeer-review

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 mitochondria) function, cytoskeleton organization, metal ion homeostasis, lipid trafficking, calcium signalling, and nutrient sensing. The mitochondria) and cytoskeletal abnormalities were validated in patient cells carrying mutations in NPC1, confirming their dysfunction in NPC disease.

Original languageEnglish
Article number201800253
Number of pages12
JournalLife Science Alliance
Volume3
Issue number7
Early online date2 Jun 2020
DOIs
StatePublished - Jul 2020

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