TY  - JOUR
A1  - Şen, Nesli Ece
A1  - Arsović, Aleksandar
A1  - Meierhofer, David
A1  - Brodesser, Susanne
A1  - Oberschmidt, Carola
A1  - Canet Pons, Júlia
A1  - Kaya, Zeynep-Ece
A1  - Halbach, Melanie Vanessa
A1  - Gispert, Suzana
A1  - Sandhoff, Konrad
A1  - Auburger, Georg
T1  - In human and mouse spino-cerebellar tissue, ataxin-2 expansion affects ceramide-sphingomyelin metabolism
T2  - International journal of molecular sciences
N2  - 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.
KW  - olivo-ponto-cerebellar atrophy (OPCA)
KW  - amyotrophic lateral sclerosis (ALS)
KW  - leukodystrophy
KW  - ceramide synthase (CERS2/CERS1)
KW  - serine palmitoyltransferase 2 (Sptlc2)
KW  - neutral sphingomyelinase (Smpd3)
KW  - neutral ceramidase (Asah2)
KW  - fatty acid elongase (Elovl1/4/5)
KW  - SCA34
KW  - SCA38
KW  - acid sphingomyelinase (ASMase; Smpd1)
Y1  - 2019
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/53282
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-532826
SN  - 1422-0067
VL  - 20
IS  - 5854
PB  - MDPI
CY  - Basel
ER  -