In Human and Mouse Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism
Autor: | Nesli-Ece Sen, Aleksandar Arsovic, David Meierhofer, Susanne Brodesser, Carola Oberschmidt, Júlia Canet-Pons, Zeynep-Ece Kaya, Melanie-Vanessa Halbach, Suzana Gispert, Konrad Sandhoff, Georg Auburger |
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Jazyk: | angličtina |
Rok vydání: | 2019 |
Předmět: |
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) Biology (General) QH301-705.5 Chemistry QD1-999 |
Zdroj: | International Journal of Molecular Sciences, Vol 20, Iss 23, p 5854 (2019) |
Druh dokumentu: | article |
ISSN: | 1422-0067 |
DOI: | 10.3390/ijms20235854 |
Popis: | 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. |
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