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Lipid metabolic perturbation is an early-onset phenotype in adult spinster mutants: a Drosophila model for lysosomal storage disorders

Intracellular accumulation of lipids and swollen dysfunctional lysosomes are linked to several neurodegenerative diseases, including lysosomal storage disorders (LSD). Detailed characterization of lipid metabolic changes in relation to the onset and progression of neurodegeneration is currently miss...

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Autores principales: Hebbar, Sarita, Khandelwal, Avinash, Jayashree, R., Hindle, Samantha J., Chiang, Yin Ning, Yew, Joanne Y., Sweeney, Sean T., Schwudke, Dominik
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5739291/
https://www.ncbi.nlm.nih.gov/pubmed/29046397
http://dx.doi.org/10.1091/mbc.E16-09-0674
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author Hebbar, Sarita
Khandelwal, Avinash
Jayashree, R.
Hindle, Samantha J.
Chiang, Yin Ning
Yew, Joanne Y.
Sweeney, Sean T.
Schwudke, Dominik
author_facet Hebbar, Sarita
Khandelwal, Avinash
Jayashree, R.
Hindle, Samantha J.
Chiang, Yin Ning
Yew, Joanne Y.
Sweeney, Sean T.
Schwudke, Dominik
author_sort Hebbar, Sarita
collection PubMed
description Intracellular accumulation of lipids and swollen dysfunctional lysosomes are linked to several neurodegenerative diseases, including lysosomal storage disorders (LSD). Detailed characterization of lipid metabolic changes in relation to the onset and progression of neurodegeneration is currently missing. We systematically analyzed lipid perturbations in spinster (spin) mutants, a Drosophila model of LSD-like neurodegeneration. Our results highlight an imbalance in brain ceramide and sphingosine in the early stages of neurodegeneration, preceding the accumulation of endomembranous structures, manifestation of altered behavior, and buildup of lipofuscin. Manipulating levels of ceramidase and altering these lipids in spin mutants allowed us to conclude that ceramide homeostasis is the driving force in disease progression and is integral to spin function in the adult nervous system. We identified 29 novel physical interaction partners of Spin and focused on the lipid carrier protein, Lipophorin (Lpp). A subset of Lpp and Spin colocalize in the brain and within organs specialized for lipid metabolism (fat bodies and oenocytes). Reduced Lpp protein was observed in spin mutant tissues. Finally, increased levels of lipid metabolites produced by oenocytes in spin mutants allude to a functional interaction between Spin and Lpp, underscoring the systemic nature of lipid perturbation in LSD.
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spelling pubmed-57392912018-03-02 Lipid metabolic perturbation is an early-onset phenotype in adult spinster mutants: a Drosophila model for lysosomal storage disorders Hebbar, Sarita Khandelwal, Avinash Jayashree, R. Hindle, Samantha J. Chiang, Yin Ning Yew, Joanne Y. Sweeney, Sean T. Schwudke, Dominik Mol Biol Cell Articles Intracellular accumulation of lipids and swollen dysfunctional lysosomes are linked to several neurodegenerative diseases, including lysosomal storage disorders (LSD). Detailed characterization of lipid metabolic changes in relation to the onset and progression of neurodegeneration is currently missing. We systematically analyzed lipid perturbations in spinster (spin) mutants, a Drosophila model of LSD-like neurodegeneration. Our results highlight an imbalance in brain ceramide and sphingosine in the early stages of neurodegeneration, preceding the accumulation of endomembranous structures, manifestation of altered behavior, and buildup of lipofuscin. Manipulating levels of ceramidase and altering these lipids in spin mutants allowed us to conclude that ceramide homeostasis is the driving force in disease progression and is integral to spin function in the adult nervous system. We identified 29 novel physical interaction partners of Spin and focused on the lipid carrier protein, Lipophorin (Lpp). A subset of Lpp and Spin colocalize in the brain and within organs specialized for lipid metabolism (fat bodies and oenocytes). Reduced Lpp protein was observed in spin mutant tissues. Finally, increased levels of lipid metabolites produced by oenocytes in spin mutants allude to a functional interaction between Spin and Lpp, underscoring the systemic nature of lipid perturbation in LSD. The American Society for Cell Biology 2017-12-15 /pmc/articles/PMC5739291/ /pubmed/29046397 http://dx.doi.org/10.1091/mbc.E16-09-0674 Text en © 2017 Hebbar et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology.
spellingShingle Articles
Hebbar, Sarita
Khandelwal, Avinash
Jayashree, R.
Hindle, Samantha J.
Chiang, Yin Ning
Yew, Joanne Y.
Sweeney, Sean T.
Schwudke, Dominik
Lipid metabolic perturbation is an early-onset phenotype in adult spinster mutants: a Drosophila model for lysosomal storage disorders
title Lipid metabolic perturbation is an early-onset phenotype in adult spinster mutants: a Drosophila model for lysosomal storage disorders
title_full Lipid metabolic perturbation is an early-onset phenotype in adult spinster mutants: a Drosophila model for lysosomal storage disorders
title_fullStr Lipid metabolic perturbation is an early-onset phenotype in adult spinster mutants: a Drosophila model for lysosomal storage disorders
title_full_unstemmed Lipid metabolic perturbation is an early-onset phenotype in adult spinster mutants: a Drosophila model for lysosomal storage disorders
title_short Lipid metabolic perturbation is an early-onset phenotype in adult spinster mutants: a Drosophila model for lysosomal storage disorders
title_sort lipid metabolic perturbation is an early-onset phenotype in adult spinster mutants: a drosophila model for lysosomal storage disorders
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5739291/
https://www.ncbi.nlm.nih.gov/pubmed/29046397
http://dx.doi.org/10.1091/mbc.E16-09-0674
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