Abstract
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.
Highlights
Spinocerebellar ataxia type 2 (SCA2) is an autosomal, dominantly inherited, multi-system neurodegenerative movement disorder [1,2,3,4,5,6] which was originally separated from other ataxias because of the early conspicuous slowing of eye tracking jumps [7,8,9,10,11]
The cerebellar tissue of a Central European spinocerebellar ataxia type 2 (SCA2) patient who was characterized in various neuropathological studies [52,55,56, 78,79,80,81,82,83,84,85,86,87,88] versus two age/sex-matched controls obtained from BrainNet-Europe underwent lipid extraction, thin layer chromatography, and densitometric quantification of the stained bands
There was a strong reduction of those lipids that are typical for the myelin sheaths around axons, namely, a decrease of sulfatide to 17% and of galactosylceramide to 25%
Summary
Spinocerebellar ataxia type 2 (SCA2) is an autosomal, dominantly inherited, multi-system neurodegenerative movement disorder [1,2,3,4,5,6] which was originally separated from other ataxias because of the early conspicuous slowing of eye tracking jumps [7,8,9,10,11] It is caused by unstable expansion mutations of a (CAG)8-CAA-(CAG)4-CAA-(CAG)8or repetitive structure that encodes a polyglutamine (polyQ) domain in ataxin-2 (gene symbol ATXN2) [12,13,14,15]. Shorter expansions of intermediate size between 27Q and 32Q increase the risk to be affected by motor neuron degeneration in amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar dementia (FTLD) [21,22,23] They elevate the risk of suffering from Parkinson’s disease variants such as progressive supranuclear palsy (PSP) [24,25,26]. The formation of aggregates of the microtubule-associated protein tau (MAPT) is similar to the neurodegenerative disorders ALS, FTLD, and PSP [27]
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