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Sphingolipid metabolism governs Purkinje cell patterned degeneration in Atxn1[82Q]/+ mice

Patterned degeneration of Purkinje cells (PCs) can be observed in a wide range of neuropathologies, but mechanisms behind nonrandom cerebellar neurodegeneration remain unclear. Sphingolipid metabolism dyshomeostasis typically leads to PC neurodegeneration; hence, we questioned whether local sphingol...

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Autores principales: Blot, François G. C., Krijnen, Wilhelmina H. J. J., Den Hoedt, Sandra, Osório, Catarina, White, Joshua J., Mulder, Monique T., Schonewille, Martijn
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8433568/
https://www.ncbi.nlm.nih.gov/pubmed/34479994
http://dx.doi.org/10.1073/pnas.2016969118
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author Blot, François G. C.
Krijnen, Wilhelmina H. J. J.
Den Hoedt, Sandra
Osório, Catarina
White, Joshua J.
Mulder, Monique T.
Schonewille, Martijn
author_facet Blot, François G. C.
Krijnen, Wilhelmina H. J. J.
Den Hoedt, Sandra
Osório, Catarina
White, Joshua J.
Mulder, Monique T.
Schonewille, Martijn
author_sort Blot, François G. C.
collection PubMed
description Patterned degeneration of Purkinje cells (PCs) can be observed in a wide range of neuropathologies, but mechanisms behind nonrandom cerebellar neurodegeneration remain unclear. Sphingolipid metabolism dyshomeostasis typically leads to PC neurodegeneration; hence, we questioned whether local sphingolipid balance underlies regional sensitivity to pathological insults. Here, we investigated the regional compartmentalization of sphingolipids and their related enzymes in the cerebellar cortex in healthy and pathological conditions. Analysis in wild-type animals revealed higher sphingosine kinase 1 (Sphk1) levels in the flocculonodular cerebellum, while sphingosine-1-phosphate (S1P) levels were higher in the anterior cerebellum. Next, we investigated a model for spinocerebellar ataxia type 1 (SCA1) driven by the transgenic expression of the expanded Ataxin 1 protein with 82 glutamine (82Q), exhibiting severe PC degeneration in the anterior cerebellum while the flocculonodular region is preserved. In Atxn1[82Q]/+ mice, we found that levels of Sphk1 and Sphk2 were region-specific decreased and S1P levels increased, particularly in the anterior cerebellum. To determine if there is a causal link between sphingolipid levels and neurodegeneration, we deleted the Sphk1 gene in Atxn1[82Q]/+ mice. Analysis of Atxn1[82Q]/+; Sphk1(−/−) mice confirmed a neuroprotective effect, rescuing a subset of PCs in the anterior cerebellum, in domains reminiscent of the modules defined by AldolaseC expression. Finally, we showed that Sphk1 deletion acts on the ATXN1[82Q] protein expression and prevents PC degeneration. Taken together, our results demonstrate that there are regional differences in sphingolipid metabolism and that this metabolism is directly involved in PC degeneration in Atxn1[82Q]/+ mice.
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spelling pubmed-84335682021-09-28 Sphingolipid metabolism governs Purkinje cell patterned degeneration in Atxn1[82Q]/+ mice Blot, François G. C. Krijnen, Wilhelmina H. J. J. Den Hoedt, Sandra Osório, Catarina White, Joshua J. Mulder, Monique T. Schonewille, Martijn Proc Natl Acad Sci U S A Biological Sciences Patterned degeneration of Purkinje cells (PCs) can be observed in a wide range of neuropathologies, but mechanisms behind nonrandom cerebellar neurodegeneration remain unclear. Sphingolipid metabolism dyshomeostasis typically leads to PC neurodegeneration; hence, we questioned whether local sphingolipid balance underlies regional sensitivity to pathological insults. Here, we investigated the regional compartmentalization of sphingolipids and their related enzymes in the cerebellar cortex in healthy and pathological conditions. Analysis in wild-type animals revealed higher sphingosine kinase 1 (Sphk1) levels in the flocculonodular cerebellum, while sphingosine-1-phosphate (S1P) levels were higher in the anterior cerebellum. Next, we investigated a model for spinocerebellar ataxia type 1 (SCA1) driven by the transgenic expression of the expanded Ataxin 1 protein with 82 glutamine (82Q), exhibiting severe PC degeneration in the anterior cerebellum while the flocculonodular region is preserved. In Atxn1[82Q]/+ mice, we found that levels of Sphk1 and Sphk2 were region-specific decreased and S1P levels increased, particularly in the anterior cerebellum. To determine if there is a causal link between sphingolipid levels and neurodegeneration, we deleted the Sphk1 gene in Atxn1[82Q]/+ mice. Analysis of Atxn1[82Q]/+; Sphk1(−/−) mice confirmed a neuroprotective effect, rescuing a subset of PCs in the anterior cerebellum, in domains reminiscent of the modules defined by AldolaseC expression. Finally, we showed that Sphk1 deletion acts on the ATXN1[82Q] protein expression and prevents PC degeneration. Taken together, our results demonstrate that there are regional differences in sphingolipid metabolism and that this metabolism is directly involved in PC degeneration in Atxn1[82Q]/+ mice. National Academy of Sciences 2021-09-07 2021-09-03 /pmc/articles/PMC8433568/ /pubmed/34479994 http://dx.doi.org/10.1073/pnas.2016969118 Text en Copyright © 2021 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Blot, François G. C.
Krijnen, Wilhelmina H. J. J.
Den Hoedt, Sandra
Osório, Catarina
White, Joshua J.
Mulder, Monique T.
Schonewille, Martijn
Sphingolipid metabolism governs Purkinje cell patterned degeneration in Atxn1[82Q]/+ mice
title Sphingolipid metabolism governs Purkinje cell patterned degeneration in Atxn1[82Q]/+ mice
title_full Sphingolipid metabolism governs Purkinje cell patterned degeneration in Atxn1[82Q]/+ mice
title_fullStr Sphingolipid metabolism governs Purkinje cell patterned degeneration in Atxn1[82Q]/+ mice
title_full_unstemmed Sphingolipid metabolism governs Purkinje cell patterned degeneration in Atxn1[82Q]/+ mice
title_short Sphingolipid metabolism governs Purkinje cell patterned degeneration in Atxn1[82Q]/+ mice
title_sort sphingolipid metabolism governs purkinje cell patterned degeneration in atxn1[82q]/+ mice
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8433568/
https://www.ncbi.nlm.nih.gov/pubmed/34479994
http://dx.doi.org/10.1073/pnas.2016969118
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