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Disruptive lysosomal-metabolic signaling and neurodevelopmental deficits that precede Purkinje cell loss in a mouse model of Niemann-Pick Type-C disease

Purkinje cell (PC) loss occurs at an early age in patients and animal models of Niemann-Pick Type C (NPC), a lysosomal storage disease caused by mutations in the Npc1 or Npc2 genes. Although degeneration of PCs occurs early in NPC, little is known about how NPC1 deficiency affects the postnatal deve...

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Autores principales: Kim, Sarah, Ochoa, Kathleen, Melli, Sierra E., Yousufzai, Fawad A. K., Barrera, Zerian D., Williams, Aela A., McIntyre, Gianna, Delgado, Esteban, Bolish, James N., Macleod, Collin M., Boghos, Mary, Lens, Hayden P., Ramos, Alex G., Wilson, Vincent B., Maloney, Kelly, Padron, Zachary M., Khan, Amaal H., Blanco, Rosa E., Soto, Ileana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10079843/
https://www.ncbi.nlm.nih.gov/pubmed/37024714
http://dx.doi.org/10.1038/s41598-023-32971-0
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author Kim, Sarah
Ochoa, Kathleen
Melli, Sierra E.
Yousufzai, Fawad A. K.
Barrera, Zerian D.
Williams, Aela A.
McIntyre, Gianna
Delgado, Esteban
Bolish, James N.
Macleod, Collin M.
Boghos, Mary
Lens, Hayden P.
Ramos, Alex G.
Wilson, Vincent B.
Maloney, Kelly
Padron, Zachary M.
Khan, Amaal H.
Blanco, Rosa E.
Soto, Ileana
author_facet Kim, Sarah
Ochoa, Kathleen
Melli, Sierra E.
Yousufzai, Fawad A. K.
Barrera, Zerian D.
Williams, Aela A.
McIntyre, Gianna
Delgado, Esteban
Bolish, James N.
Macleod, Collin M.
Boghos, Mary
Lens, Hayden P.
Ramos, Alex G.
Wilson, Vincent B.
Maloney, Kelly
Padron, Zachary M.
Khan, Amaal H.
Blanco, Rosa E.
Soto, Ileana
author_sort Kim, Sarah
collection PubMed
description Purkinje cell (PC) loss occurs at an early age in patients and animal models of Niemann-Pick Type C (NPC), a lysosomal storage disease caused by mutations in the Npc1 or Npc2 genes. Although degeneration of PCs occurs early in NPC, little is known about how NPC1 deficiency affects the postnatal development of PCs. Using the Npc1(nmf164) mouse model, we found that NPC1 deficiency significantly affected the postnatal development of PC dendrites and synapses. The developing dendrites of Npc1(nmf164) PCs were significantly deficient in mitochondria and lysosomes. Furthermore, anabolic (mTORC1) and catabolic (TFEB) signaling pathways were not only perturbed but simultaneously activated in NPC1-deficient PCs, suggesting a loss of metabolic balance. We also found that mice with conditional heterozygous deletion of the Phosphatase and Tensin Homolog Deleted on Chromosome 10 gene (Pten-cHet), an inhibitor of mTORC1, showed similar early dendritic alterations in PCs to those found in Npc1-deficient mice. However, in contrast to Npc1(nmf164) mice, Pten-cHet mice exhibited the overactivation of the mTORC1 pathway but with a strong inhibition of TFEB signaling, along with no dendritic mitochondrial reductions by the end of their postnatal development. Our data suggest that disruption of the lysosomal-metabolic signaling in PCs causes dendritic and synaptic developmental deficits that precede and promote their early degeneration in NPC.
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spelling pubmed-100798432023-04-08 Disruptive lysosomal-metabolic signaling and neurodevelopmental deficits that precede Purkinje cell loss in a mouse model of Niemann-Pick Type-C disease Kim, Sarah Ochoa, Kathleen Melli, Sierra E. Yousufzai, Fawad A. K. Barrera, Zerian D. Williams, Aela A. McIntyre, Gianna Delgado, Esteban Bolish, James N. Macleod, Collin M. Boghos, Mary Lens, Hayden P. Ramos, Alex G. Wilson, Vincent B. Maloney, Kelly Padron, Zachary M. Khan, Amaal H. Blanco, Rosa E. Soto, Ileana Sci Rep Article Purkinje cell (PC) loss occurs at an early age in patients and animal models of Niemann-Pick Type C (NPC), a lysosomal storage disease caused by mutations in the Npc1 or Npc2 genes. Although degeneration of PCs occurs early in NPC, little is known about how NPC1 deficiency affects the postnatal development of PCs. Using the Npc1(nmf164) mouse model, we found that NPC1 deficiency significantly affected the postnatal development of PC dendrites and synapses. The developing dendrites of Npc1(nmf164) PCs were significantly deficient in mitochondria and lysosomes. Furthermore, anabolic (mTORC1) and catabolic (TFEB) signaling pathways were not only perturbed but simultaneously activated in NPC1-deficient PCs, suggesting a loss of metabolic balance. We also found that mice with conditional heterozygous deletion of the Phosphatase and Tensin Homolog Deleted on Chromosome 10 gene (Pten-cHet), an inhibitor of mTORC1, showed similar early dendritic alterations in PCs to those found in Npc1-deficient mice. However, in contrast to Npc1(nmf164) mice, Pten-cHet mice exhibited the overactivation of the mTORC1 pathway but with a strong inhibition of TFEB signaling, along with no dendritic mitochondrial reductions by the end of their postnatal development. Our data suggest that disruption of the lysosomal-metabolic signaling in PCs causes dendritic and synaptic developmental deficits that precede and promote their early degeneration in NPC. Nature Publishing Group UK 2023-04-06 /pmc/articles/PMC10079843/ /pubmed/37024714 http://dx.doi.org/10.1038/s41598-023-32971-0 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/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. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Kim, Sarah
Ochoa, Kathleen
Melli, Sierra E.
Yousufzai, Fawad A. K.
Barrera, Zerian D.
Williams, Aela A.
McIntyre, Gianna
Delgado, Esteban
Bolish, James N.
Macleod, Collin M.
Boghos, Mary
Lens, Hayden P.
Ramos, Alex G.
Wilson, Vincent B.
Maloney, Kelly
Padron, Zachary M.
Khan, Amaal H.
Blanco, Rosa E.
Soto, Ileana
Disruptive lysosomal-metabolic signaling and neurodevelopmental deficits that precede Purkinje cell loss in a mouse model of Niemann-Pick Type-C disease
title Disruptive lysosomal-metabolic signaling and neurodevelopmental deficits that precede Purkinje cell loss in a mouse model of Niemann-Pick Type-C disease
title_full Disruptive lysosomal-metabolic signaling and neurodevelopmental deficits that precede Purkinje cell loss in a mouse model of Niemann-Pick Type-C disease
title_fullStr Disruptive lysosomal-metabolic signaling and neurodevelopmental deficits that precede Purkinje cell loss in a mouse model of Niemann-Pick Type-C disease
title_full_unstemmed Disruptive lysosomal-metabolic signaling and neurodevelopmental deficits that precede Purkinje cell loss in a mouse model of Niemann-Pick Type-C disease
title_short Disruptive lysosomal-metabolic signaling and neurodevelopmental deficits that precede Purkinje cell loss in a mouse model of Niemann-Pick Type-C disease
title_sort disruptive lysosomal-metabolic signaling and neurodevelopmental deficits that precede purkinje cell loss in a mouse model of niemann-pick type-c disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10079843/
https://www.ncbi.nlm.nih.gov/pubmed/37024714
http://dx.doi.org/10.1038/s41598-023-32971-0
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