In Human and Mouse Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism
| العنوان: | In Human and Mouse Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism |
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| المؤلفون: | Georg Auburger, Susanne Brodesser, Zeynep-Ece Kaya, Júlia Canet-Pons, Aleksandar Arsovic, Carola Oberschmidt, Nesli-Ece Sen, Suzana Gispert, Konrad Sandhoff, Melanie-Vanessa Halbach, David Meierhofer |
| المساهمون: | İÜC, Cerrahpaşa Tıp Fakültesi, Dahili Tıp Bilimleri Bölümü |
| المصدر: | International Journal of Molecular Sciences, Vol 20, Iss 23, p 5854 (2019) International Journal of Molecular Sciences Volume 20 Issue 23 |
| بيانات النشر: | MDPI AG, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | acid sphingomyelinase (ASMase, leukodystrophy, amyotrophic lateral sclerosis (ALS), neutral sphingomyelinase (Smpd3), neutral ceramidase (asah2), serine palmitoyltransferase 2 (sptlc2), smpd1), lcsh:Chemistry, Myelin, chemistry.chemical_compound, fatty acid elongase (Elovl1/4/5), Sphingosine N-Acyltransferase, lcsh:QH301-705.5, Spectroscopy, Ataxin-2, Mice, Knockout, General Medicine, Computer Science Applications, Cell biology, Sphingomyelins, SCA38, medicine.anatomical_structure, Sphingomyelin Phosphodiesterase, amyotrophic lateral sclerosis (als), acid sphingomyelinase (asmase, SCA34, Knockout mouse, Spinocerebellar ataxia, sca34, lipids (amino acids, peptides, and proteins), Sphingomyelin, sca38, Ceramide, olivo-ponto-cerebellar atrophy (opca), Biology, Ceramides, Catalysis, Article, Inorganic Chemistry, ddc:570, medicine, Animals, Humans, Spinocerebellar Ataxias, serine palmitoyltransferase 2 (Sptlc2), ddc:610, Physical and Theoretical Chemistry, Eye Proteins, Molecular Biology, Smpd1), Sphingosine, fatty acid elongase (elovl1/4/5), Nervous tissue, Organic Chemistry, Membrane Proteins, olivo-ponto-cerebellar atrophy (OPCA), medicine.disease, Lipid Metabolism, ceramide synthase (cers2/cers1), Disease Models, Animal, chemistry, lcsh:Biology (General), lcsh:QD1-999, Ataxin, neutral sphingomyelinase (smpd3), neutral ceramidase (Asah2), ceramide synthase (CERS2/CERS1), Trinucleotide Repeat Expansion |
| الوصف: | 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&ndash 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. |
| وصف الملف: | application/pdf; application/zip; application/octet-stream |
| اللغة: | English |
| تدمد: | 1422-0067 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d375b355a0af0e0d43d23b91b974bbe0Test https://www.mdpi.com/1422-0067/20/23/5854Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....d375b355a0af0e0d43d23b91b974bbe0 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14220067 |
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