Trehalose enhances mitochondria deficits in human NPC1 mutant fibroblasts but disrupts mouse Purkinje cell dendritic growth ex vivo.

Authors

Collin M MacLeod
Fawad A K Yousufzai, Rowan University
Liam T Spencer
Sarah Kim, Rowan University
Lucianne A Rivera-Rosario
Zerian D Barrera, Rowan University
Lindsay Walsh
Claude Krummenacher, Rowan UniversityFollow
Benjamin Carone, Rowan UniversityFollow
Ileana Soto

Document Type

Article

Version Deposited

Published Version

Publication Date

11-30-2023

Publication Title

PLoS One

DOI

10.1371/journal.pone.0294312

Abstract

Lysosomes play important roles in catabolism, nutrient sensing, metabolic signaling, and homeostasis. NPC1 deficiency disrupts lysosomal function by inducing cholesterol accumulation that leads to early neurodegeneration in Niemann-Pick type C (NPC) disease. Mitochondria pathology and deficits in NPC1 deficient cells are associated with impaired lysosomal proteolysis and metabolic signaling. It is thought that activation of the transcription factor TFEB, an inducer of lysosome biogenesis, restores lysosomal-autophagy activity in lysosomal storage disorders. Here, we investigated the effect of trehalose, a TFEB activator, in the mitochondria pathology of NPC1 mutant fibroblasts in vitro and in mouse developmental Purkinje cells ex vivo. We found that in NPC1 mutant fibroblasts, serum starvation or/and trehalose treatment, both activators of TFEB, reversed mitochondria fragmentation to a more tubular mitochondrion. Trehalose treatment also decreased the accumulation of Filipin+ cholesterol in NPC1 mutant fibroblasts. However, trehalose treatment in cerebellar organotypic slices (COSCs) from wild-type and Npc1nmf164 mice caused mitochondria fragmentation and lack of dendritic growth and degeneration in developmental Purkinje cells. Our data suggest, that although trehalose successfully restores mitochondria length and decreases cholesterol accumulation in NPC1 mutant fibroblasts, in COSCs, Purkinje cells mitochondria and dendritic growth are negatively affected possibly through the overactivation of the TFEB-lysosomal-autophagy pathway.

Comments

Copyright: © 2023 MacLeod et al. This is an open access article distributed under the terms of the Creative Commons Attribution License,.

Recommended Citation

MacLeod CM, Yousufzai FAK, Spencer LT, Kim S, Rivera-Rosario LA, Barrera ZD, et al. (2023) Trehalose enhances mitochondria deficits in human NPC1 mutant fibroblasts but disrupts mouse Purkinje cell dendritic growth ex vivo. PLoS ONE 18(11): e0294312. https://doi.org/10.1371/journal.pone.0294312

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.