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

François G.C. Blot*, Wilhelmina H.J.J. Krijnen, Sandra Den Hoedt, Catarina Osório, Joshua J. White, Monique T. Mulder, Martijn Schonewille

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Article numbere2016969118
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number36
Publication statusPublished - 7 Sept 2021

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. We thank Dr. Dick Jaarsma for his feedback and years of mentorship of F.G.C.B.; Dr. Harry T. Orr, who provided the Atxn1[82Q]/+ mice; Dr. Huda Zhogbi, who provided the anti-ATXN1 antibody; Dr. Chris I. De Zeeuw, Dr. Laurens W. J. Bosman, and Bram W. Kuppens for their cooperative work on the Atxn1[82Q]/+ mice; the board members of the Sphingolipid Club for providing an open environment for biochemists and nonbiochemists; and Laura Post for technical assistance. This work was supported by Nederlandse organisatie voor Wetenschappelijk Onderzoek NWO-ZonMw (to C.O.) and NWO-Veni (to J.J.W.) and European Research Council Starter Grant ERC-Stg 680235 (to M.S.).

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