A fungal plant infection model recapitulates Niemann–Pick type C pathogenesis and enables therapeutic evaluation

Niemann–Pick type C (NPC) 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 and phenotypically robust eukaryotic model of NPC. Introduction of disease-associated point mutations into CoNpc1 or CoNpc2 abolished pathogenicity, demonstrating that NPC dysfunction compromises lipid-dependent morphogenesis essential for host penetration. Expression of human NPC1 complemented the fungal deletion mutant, highlighting conserved sterol transport functions across kingdoms. Pharmacological treatments with miglustat and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) restored pathogenicity through distinct lipid pathways: miglustat normalized sphingolipid metabolism, whereas HP-β-CD alleviated sterol mislocalization. These complementary rescue routes reveal that perturbations in NPC homologs converge on lipid-dependent morphogenesis closely linked to actin organization. By linking lipid metabolism, actin cytoskeletal organization, and pharmacological rescue to a measurable infection outcome, this fungal model provides a tractable and biologically faithful platform for mechanistic and therapeutic exploration in NPC disease.