A Colletotrichum orbiculare-based fungal model recapitulates conserved cellular defects of Niemann–Pick type C disease and enables therapeutic evaluation

Abstract Niemann–Pick type C disease is a fatal lysosomal storage disorder caused by mutations in NPC1 or NPC2 , leading to lipid accumulation and progressive neurodegeneration. Current mammalian models recapitulate major pathological features but are limited by long disease courses and low throughput. Here, we establish the plant-pathogenic fungus Colletotrichum orbiculare as a scalable eukaryotic model of Niemann–Pick type C disease. Introduction of disease-associated mutations into fungal NPC1 or NPC2 homologs abolishes pathogenicity, showing that NPC dysfunction compromises lipid-dependent morphogenesis required for host penetration. Conversely, human NPC1 partially restores fungal infection. Together, these findings support functional conservation of NPC-dependent cellular processes across kingdoms. Miglustat and 2-hydroxypropyl-β-cyclodextrin restore pathogenicity through distinct lipid pathways. These complementary modes of rescue indicate that NPC1 and NPC2 dysfunction converges on lipid-dependent morphogenesis closely linked to actin organization. By connecting lipid metabolism, actin organization, and pharmacological rescue to a measurable infection outcome, this fungal model provides a tractable and scalable platform for mechanistic and therapeutic exploration.