In Human and Mouse Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism
In Human and Mouse Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism
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DOI：
10.3390/ijms20235854
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发表时间：
2019-12-01
影响因子：
5.6
通讯作者：
Auburger, Georg
中科院分区：
文献类型：
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作者：
Sen, Nesli-Ece;Arsovic, Aleksandar;Auburger, Georg
Ataxin-2（人类基因符号 ATXN2）在应激反应过程中发挥作用，调节 mRNA 翻译和营养代谢。 Ataxin-2 基因敲除小鼠表现出进行性肥胖、血脂异常和胰岛素抵抗。相反，由于多聚谷氨酰胺 (polyQ) 扩张，ATXN2 的功能逐渐增强，导致显性遗传的神经退行性过程，称为脊髓小脑共济失调 2 型 (SCA2)，并伴有早期脂肪组织损失和晚期肌肉萎缩。我们试图了解 SCA2 患者大脑和真实小鼠模型中的脂质失调。将患者小脑的薄层色谱与 Atxn2-CAG100-Knockin (KIN) 小鼠脊髓小脑组织的脂质代谢组进行比较。尽管 C18-神经鞘磷脂水平相当正常，但人类病理学导致脑硫苷脂、半乳糖神经酰胺、胆固醇、C22/24-神经鞘磷脂和神经节苷脂 GM1a/GD1b 缺乏。 KIN 小鼠的小脑和脊髓显示各种神经酰胺持续减少，而受影响更严重的脊髓中鞘氨醇显着升高。 C24/26-鞘磷脂缺乏与C18/20-鞘磷脂过量形成对比。脊髓小脑表达谱显示 CERS 蛋白亚型、Sptlc2 和 Smpd3 持续减少，但 Cers2 mRNA 上调，这是神经酰胺-鞘氨醇代谢的显着异常。 Asah2 mRNA 的减少与 S1P 水平缺陷相关。此外，延长酶 Elovl1、Elovl4、Elovl5 mRNA 和 ELOVL4 蛋白的下调解释了极长链鞘磷脂的缺陷。 ASMase 蛋白水平降低与长链鞘磷脂的积累相关。总体而言，在预末期的 SCA2 神经组织中，髓磷脂脂质的缺乏很明显，并且不能通过几种代谢酶的转录适应来补偿。髓鞘形成由 mTORC1 信号控制；因此，我们对人类和小鼠的观察结果与 ATXN2 酵母、线虫和小鼠直系同源物作为 mTORC1 抑制剂和自噬促进剂的已知作用一致。
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.