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