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

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.

We thank the Research Association for Biotechnology, Dr Yoshihide Hayashizaki (RIKEN), and Dr Sumio Sugano (University of Tokyo) for providing the IRAL004K24 clone (cat. HGY081864) through the National BioResource Project (MEXT, Japan). We gratefully acknowledge Dr.

Yusuke Masuo (Faculty of Pharmacy, Kanazawa University) for kindly allowing the use of the LCMS-9030 system (Shimadzu Corporation, Kyoto, Japan) and for his valuable assistance with mass spectrometric analyses. This study was supported by the Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research (JSPS KAKENHI Grants; 24K21258 and 24K01762 to Y.K. and 23K13956 to S.K.). Faculty of Agriculture, Setsunan University, Osaka, Japan Hodaka Sano, Shun Takezawa, Naoya Saomoto, Ayaka Chiba, Chikako Tanaka, Naoki Kato, Sayo Kodama & Yasuyuki Kubo Bioscience Core Facility, Kanazawa University, Kanazawa, Japan Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan The authors declare no competing interests.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material.