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

Int J Mol Sci. 2019 Nov 21;20(23):5854. doi: 10.3390/ijms20235854.


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.

Keywords: SCA34; SCA38; Smpd1); acid sphingomyelinase (ASMase; amyotrophic lateral sclerosis (ALS); ceramide synthase (CERS2/CERS1); fatty acid elongase (Elovl1/4/5); leukodystrophy; neutral ceramidase (Asah2); neutral sphingomyelinase (Smpd3); olivo-ponto-cerebellar atrophy (OPCA); serine palmitoyltransferase 2 (Sptlc2).

MeSH terms

  • Animals
  • Ataxin-2 / genetics*
  • Ataxin-2 / metabolism
  • Ceramides / metabolism*
  • Disease Models, Animal
  • Eye Proteins / genetics
  • Eye Proteins / metabolism
  • Humans
  • Lipid Metabolism / genetics
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice, Knockout
  • Sphingomyelin Phosphodiesterase / genetics
  • Sphingomyelin Phosphodiesterase / metabolism
  • Sphingomyelins / metabolism*
  • Sphingosine N-Acyltransferase / genetics
  • Sphingosine N-Acyltransferase / metabolism
  • Spinocerebellar Ataxias / genetics*
  • Spinocerebellar Ataxias / metabolism
  • Spinocerebellar Ataxias / pathology
  • Trinucleotide Repeat Expansion / genetics*


  • Ataxin-2
  • Ceramides
  • Elovl4 protein, mouse
  • Eye Proteins
  • Membrane Proteins
  • Sphingomyelins
  • Cers2 protein, mouse
  • Sphingosine N-Acyltransferase
  • Smpd3 protein, mouse
  • Sphingomyelin Phosphodiesterase