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Open AccessArticle

In Human and Mouse Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism

1
Experimental Neurology, Building 89, Goethe University Medical Faculty, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany
2
Faculty of Biosciences, Goethe-University, 60438 Frankfurt am Main, Germany
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Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin, Germany
4
Membrane Biology and Lipid Biochemistry Unit, Life and Medical Sciences Institute, University of Bonn, 53121 Bonn, Germany
5
Cerrahpasa School of Medicine, Istanbul University, 34098 Istanbul, Turkey
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(23), 5854; https://doi.org/10.3390/ijms20235854
Received: 4 November 2019 / Revised: 19 November 2019 / Accepted: 20 November 2019 / Published: 21 November 2019
(This article belongs to the Special Issue ATXN2 in Health and Disease)
Ataxin-2 (human gene symbol ATXN2) acts during stress responses, modulating mRNA translation and nutrient metabolism. Ataxin-2 knockout mice exhibit progressive obesity, dyslipidemia, and insulin resistance. Conversely, the progressive ATXN2 gain of function due to the fact of polyglutamine (polyQ) expansions leads to a dominantly inherited neurodegenerative process named spinocerebellar ataxia type 2 (SCA2) with early adipose tissue loss and late muscle atrophy. We tried to understand lipid dysregulation in a SCA2 patient brain and in an authentic mouse model. Thin layer chromatography of a patient cerebellum was compared to the lipid metabolome of Atxn2-CAG100-Knockin (KIN) mouse spinocerebellar tissue. The human pathology caused deficits of sulfatide, galactosylceramide, cholesterol, C22/24-sphingomyelin, and gangliosides GM1a/GD1b despite quite normal levels of C18-sphingomyelin. Cerebellum and spinal cord from the KIN mouse showed a consistent decrease of various ceramides with a significant elevation of sphingosine in the more severely affected spinal cord. Deficiency of C24/26-sphingomyelins contrasted with excess C18/20-sphingomyelin. Spinocerebellar expression profiling revealed consistent reductions of CERS protein isoforms, Sptlc2 and Smpd3, but upregulation of Cers2 mRNA, as prominent anomalies in the ceramide–sphingosine metabolism. Reduction of Asah2 mRNA correlated to deficient S1P levels. In addition, downregulations for the elongase Elovl1, Elovl4, Elovl5 mRNAs and ELOVL4 protein explain the deficit of very long-chain sphingomyelin. Reduced ASMase protein levels correlated to the accumulation of long-chain sphingomyelin. Overall, a deficit of myelin lipids was prominent in SCA2 nervous tissue at prefinal stage and not compensated by transcriptional adaptation of several metabolic enzymes. Myelination is controlled by mTORC1 signals; thus, our human and murine observations are in agreement with the known role of ATXN2 yeast, nematode, and mouse orthologs as mTORC1 inhibitors and autophagy promoters. View Full-Text
Keywords: olivo-ponto-cerebellar atrophy (OPCA); amyotrophic lateral sclerosis (ALS); leukodystrophy; ceramide synthase (CERS2/CERS1); serine palmitoyltransferase 2 (Sptlc2); neutral sphingomyelinase (Smpd3); neutral ceramidase (Asah2); fatty acid elongase (Elovl1/4/5); SCA34; SCA38; acid sphingomyelinase (ASMase; Smpd1) olivo-ponto-cerebellar atrophy (OPCA); amyotrophic lateral sclerosis (ALS); leukodystrophy; ceramide synthase (CERS2/CERS1); serine palmitoyltransferase 2 (Sptlc2); neutral sphingomyelinase (Smpd3); neutral ceramidase (Asah2); fatty acid elongase (Elovl1/4/5); SCA34; SCA38; acid sphingomyelinase (ASMase; Smpd1)
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Sen, N.-E.; Arsovic, A.; Meierhofer, D.; Brodesser, S.; Oberschmidt, C.; Canet-Pons, J.; Kaya, Z.-E.; Halbach, M.-V.; Gispert, S.; Sandhoff, K.; Auburger, G. In Human and Mouse Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism. Int. J. Mol. Sci. 2019, 20, 5854.

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