Ceramides And Stress Signalling Intersect With Autophagic Defects In Neurodegenerative Drosophila blue cheese (bchs) Mutants
Sphingolipid metabolites are involved in the regulation of autophagy, a degradative recycling process that is required to prevent neuronal degeneration. Drosophila blue cheese mutants neurodegenerate due to perturbations in autophagic flux, and consequent accumulation of ubiquitinated aggregates. He...
Saved in:
Main Authors: | , , , , , , , , , , , , |
---|---|
Other Authors: | |
Format: | Article |
Language: | English |
Published: |
2016
|
Subjects: | |
Online Access: | https://hdl.handle.net/10356/81549 http://hdl.handle.net/10220/39562 |
Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
Institution: | Nanyang Technological University |
Language: | English |
id |
sg-ntu-dr.10356-81549 |
---|---|
record_format |
dspace |
spelling |
sg-ntu-dr.10356-815492023-02-28T16:59:36Z Ceramides And Stress Signalling Intersect With Autophagic Defects In Neurodegenerative Drosophila blue cheese (bchs) Mutants Papan, Cyrus Osborne, Kathleen Amy Torta, Federico Shevchenko, Andrej Schwudke, Dominik Kraut, Rachel Hebbar, Sarita Sahoo, Ishtapran Matysik, Artur Garcia, Irene Argudo Narayanaswamy, Pradeep Fun, Xiu Hui Wenk, Markus R School of Biological Sciences Biological Sciences Sphingolipid metabolites are involved in the regulation of autophagy, a degradative recycling process that is required to prevent neuronal degeneration. Drosophila blue cheese mutants neurodegenerate due to perturbations in autophagic flux, and consequent accumulation of ubiquitinated aggregates. Here, we demonstrate that blue cheese mutant brains exhibit an elevation in total ceramide levels; surprisingly, however, degeneration is ameliorated when the pool of available ceramides is further increased, and exacerbated when ceramide levels are decreased by altering sphingolipid catabolism or blocking de novo synthesis. Exogenous ceramide is seen to accumulate in autophagosomes, which are fewer in number and show less efficient clearance in blue cheese mutant neurons. Sphingolipid metabolism is also shifted away from salvage toward de novo pathways, while pro-growth Akt and MAP pathways are down-regulated, and ER stress is increased. All these defects are reversed under genetic rescue conditions that increase ceramide generation from salvage pathways. This constellation of effects suggests a possible mechanism whereby the observed deficit in a potentially ceramide-releasing autophagic pathway impedes survival signaling and exacerbates neuronal death. ASTAR (Agency for Sci., Tech. and Research, S’pore) MOE (Min. of Education, S’pore) Published version 2016-01-05T06:02:40Z 2019-12-06T14:33:31Z 2016-01-05T06:02:40Z 2019-12-06T14:33:31Z 2015 Journal Article Hebbar, S., Sahoo, I., Matysik, A., Garcia, I. A., Osborne, K. A., Papan, C., et al. (2015). Ceramides And Stress Signalling Intersect With Autophagic Defects In Neurodegenerative Drosophila blue cheese (bchs) Mutants. Scientific Reports, 5, 15926-. 2045-2322 https://hdl.handle.net/10356/81549 http://hdl.handle.net/10220/39562 10.1038/srep15926 26639035 en Scientific Reports © 2015 Hebbar, S. et al. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ 18 p. application/pdf |
institution |
Nanyang Technological University |
building |
NTU Library |
continent |
Asia |
country |
Singapore Singapore |
content_provider |
NTU Library |
collection |
DR-NTU |
language |
English |
topic |
Biological Sciences |
spellingShingle |
Biological Sciences Papan, Cyrus Osborne, Kathleen Amy Torta, Federico Shevchenko, Andrej Schwudke, Dominik Kraut, Rachel Hebbar, Sarita Sahoo, Ishtapran Matysik, Artur Garcia, Irene Argudo Narayanaswamy, Pradeep Fun, Xiu Hui Wenk, Markus R Ceramides And Stress Signalling Intersect With Autophagic Defects In Neurodegenerative Drosophila blue cheese (bchs) Mutants |
description |
Sphingolipid metabolites are involved in the regulation of autophagy, a degradative recycling process that is required to prevent neuronal degeneration. Drosophila blue cheese mutants neurodegenerate due to perturbations in autophagic flux, and consequent accumulation of ubiquitinated aggregates. Here, we demonstrate that blue cheese mutant brains exhibit an elevation in total ceramide levels; surprisingly, however, degeneration is ameliorated when the pool of available ceramides is further increased, and exacerbated when ceramide levels are decreased by altering sphingolipid catabolism or blocking de novo synthesis. Exogenous ceramide is seen to accumulate in autophagosomes, which are fewer in number and show less efficient clearance in blue cheese mutant neurons. Sphingolipid metabolism is also shifted away from salvage toward de novo pathways, while pro-growth Akt and MAP pathways are down-regulated, and ER stress is increased. All these defects are reversed under genetic rescue conditions that increase ceramide generation from salvage pathways. This constellation of effects suggests a possible mechanism whereby the observed deficit in a potentially ceramide-releasing autophagic pathway impedes survival signaling and exacerbates neuronal death. |
author2 |
School of Biological Sciences |
author_facet |
School of Biological Sciences Papan, Cyrus Osborne, Kathleen Amy Torta, Federico Shevchenko, Andrej Schwudke, Dominik Kraut, Rachel Hebbar, Sarita Sahoo, Ishtapran Matysik, Artur Garcia, Irene Argudo Narayanaswamy, Pradeep Fun, Xiu Hui Wenk, Markus R |
format |
Article |
author |
Papan, Cyrus Osborne, Kathleen Amy Torta, Federico Shevchenko, Andrej Schwudke, Dominik Kraut, Rachel Hebbar, Sarita Sahoo, Ishtapran Matysik, Artur Garcia, Irene Argudo Narayanaswamy, Pradeep Fun, Xiu Hui Wenk, Markus R |
author_sort |
Papan, Cyrus |
title |
Ceramides And Stress Signalling Intersect With Autophagic Defects In Neurodegenerative Drosophila blue cheese (bchs) Mutants |
title_short |
Ceramides And Stress Signalling Intersect With Autophagic Defects In Neurodegenerative Drosophila blue cheese (bchs) Mutants |
title_full |
Ceramides And Stress Signalling Intersect With Autophagic Defects In Neurodegenerative Drosophila blue cheese (bchs) Mutants |
title_fullStr |
Ceramides And Stress Signalling Intersect With Autophagic Defects In Neurodegenerative Drosophila blue cheese (bchs) Mutants |
title_full_unstemmed |
Ceramides And Stress Signalling Intersect With Autophagic Defects In Neurodegenerative Drosophila blue cheese (bchs) Mutants |
title_sort |
ceramides and stress signalling intersect with autophagic defects in neurodegenerative drosophila blue cheese (bchs) mutants |
publishDate |
2016 |
url |
https://hdl.handle.net/10356/81549 http://hdl.handle.net/10220/39562 |
_version_ |
1759855041782480896 |