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.
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BibTeX
@article{sano2026colletotrichum,
title = {{A Colletotrichum orbiculare-based fungal model recapitulates conserved cellular defects of Niemann–Pick type C disease and enables therapeutic evaluation}},
author = {Hodaka Sano and Shun Takezawa and Naoya Saomoto and Ayaka Chiba and Chikako Tanaka and Naoki Kato and Takumi Nishiuchi and Hikari Nishisaka and Kazuyuki Kitatani and Sayo Kodama and Yasuyuki Kubo},
journal = {Communications Biology},
year = {2026},
month = oct,
doi = {10.1038/s42003-026-11198-5},
url = {https://www.nature.com/articles/s42003-026-11198-5},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A Colletotrichum orbiculare-based fungal model recapitulates conserved cellular defects of Niemann–Pick type C disease and enables therapeutic evaluation
AU - Hodaka Sano
AU - Shun Takezawa
AU - Naoya Saomoto
AU - Ayaka Chiba
AU - Chikako Tanaka
AU - Naoki Kato
AU - Takumi Nishiuchi
AU - Hikari Nishisaka
AU - Kazuyuki Kitatani
AU - Sayo Kodama
AU - Yasuyuki Kubo
PY - 2026
DA - 2026/10/17
JO - Communications Biology
DO - 10.1038/s42003-026-11198-5
UR - https://www.nature.com/articles/s42003-026-11198-5
AB - 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.
SN - 2399-3642
ER -