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

Sen, N.-E., Arsovic, A., Meierhofer, D., Brodesser, S., Oberschmidt, C., Canet-Pons, J., et al. (2019). In Human and Mouse Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism. International Journal of Molecular Sciences, 2019(20): 5854. doi:10.3390/ijms20235854.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0005-4955-A Version Permalink: http://hdl.handle.net/21.11116/0000-0005-4956-9
Genre: Journal Article

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 Creators:
Sen, Nesli-Ece , Author
Arsovic, Aleksandar , Author
Meierhofer, David1, Author              
Brodesser, Susanne , Author
Oberschmidt, Carola , Author
Canet-Pons, Júlia , Author
Kaya, Zeynep-Ece, Author
Halbach, Melanie-Vanessa , Author
Gispert, Suzana , Author
Sandhoff, Konrad , Author
Auburger, Georg , Author
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1Mass Spectrometry (Head: David Meierhofer), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479669              

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Free keywords: olivo-ponto-cerebellar atrophy (OPCA); amyotrophic lateral sclerosis (ALS); leukodystrophy; ceramide synthase (CERS2/CERS1); serine palmitoyltransferase 2 (Sptlc2); neutral sphingomyelinase(Smpd3);neutralceramidase(Asah2);fattyacidelongase(Elovl1/4/5);SCA34;SCA38; acid sphingomyelinase (ASMase; Smpd1)
 Abstract: Ataxin-2 (human gene symbol ATXN2) acts during stress responses, modulating mRNA translationandnutrientmetabolism. Ataxin-2knockoutmiceexhibitprogressiveobesity,dyslipidemia, and insulin resistance. Conversely, the progressive ATXN2 gain of function due to the fact of polyglutamine(polyQ)expansionsleadstoadominantlyinheritedneurodegenerativeprocessnamed 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.

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Language(s): eng - English
 Dates: 2019-11-202019-11-21
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.3390/ijms20235854
 Degree: -

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Title: International Journal of Molecular Sciences
  Abbreviation : Int. J. Mol. Sci.
Source Genre: Journal
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Publ. Info: Basel, Switzerland : MDPI AG
Pages: - Volume / Issue: 2019 (20) Sequence Number: 5854 Start / End Page: - Identifier: ISSN: 1422-0067
CoNE: https://pure.mpg.de/cone/journals/resource/1422-0067