Sphingolipid metabolism governs Purkinje cell patterned degeneration in Atxn1[82Q]/+ mice.
Sphingolipid metabolism governs Purkinje cell patterned degeneration in Atxn1[82Q]/+ mice.
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DOI：
10.1073/pnas.2016969118
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发表时间：
2021-09-07
影响因子：
11.1
通讯作者：
Schonewille M
中科院分区：
文献类型：
--
作者：
Blot FGC;Krijnen WHJJ;Den Hoedt S;Osório C;White JJ;Mulder MT;Schonewille M
神经元亚型受到神经病理学的不同影响。例如，浦肯野细胞，小脑的主要神经元，可以根据它们对病理损伤的敏感性分为亚群。然而，解释为什么在看似相同的神经元中，一些会退化而另一些会存活的分子机制仍然未知。在这里，我们分析了，在小脑神经变性的疾病模型，鞘脂的代谢，复杂的脂质参与细胞凋亡，并发现特定的鞘脂积累在小脑区域主要受神经变性。通过基因突变破坏鞘脂代谢来防止这种积累，对浦肯野细胞亚群产生神经保护作用。因此，我们的数据表明，鞘脂代谢参与神经元亚型神经变性的易感性。浦肯野细胞（PC）的模式化变性可以在广泛的神经病理学中观察到，但非随机小脑神经变性背后的机制仍不清楚。鞘脂代谢失调通常会导致PC神经变性，因此，我们质疑局部鞘脂平衡是否是区域对病理损伤敏感性的基础。在这里，我们研究了健康和病理条件下小脑皮质中鞘脂及其相关酶的区域区室化。在野生型动物中的分析显示，在绒球结节小脑中鞘氨醇激酶1（Sphk 1）水平较高，而鞘氨醇-1-磷酸（S1 P）水平在小脑前部较高。接下来，我们研究了脊髓小脑性共济失调1型（SCA 1）的模型驱动的扩展Ataxin 1蛋白与82谷氨酰胺（82 Q）的转基因表达，表现出严重的PC变性在小脑前部，而绒球结节区被保留。在Atxn 1 [82 Q]/+小鼠中，我们发现Sphk 1和Sphk 2的水平具有区域特异性降低，S1 P水平升高，特别是在小脑前部。为了确定鞘脂水平和神经变性之间是否存在因果关系，我们删除了Atxn 1 [82 Q]/+小鼠中的Sphk 1基因。对Atxn 1 [82 Q]/+; Sphk 1 −/−小鼠的分析证实了神经保护作用，挽救了小脑前部的PC亚群，这些PC亚群位于让人想起由AldolaseC表达定义的模块的区域。最后，我们发现Sphk 1缺失对ATXN 1 [82 Q]蛋白表达起作用，并阻止PC变性。综上所述，我们的结果表明，鞘脂代谢存在区域差异，并且这种代谢直接参与Atxn 1 [82 Q]/+小鼠的PC变性。
Neuronal subtypes are differentially affected by neuropathologies. For example, Purkinje cells, the principal neurons of the cerebellum, can be divided in subpopulations based on their sensitivity to pathological insult. However, the molecular mechanisms explaining why, among seemingly identical neurons, some will degenerate while others survive remain unknown. Here, we analyzed, in a disease model of cerebellar neurodegeneration, the metabolism of sphingolipids, complex lipids involved in cell apoptosis, and found that specific sphingolipids accumulate in the cerebellar region primarily affected by neurodegeneration. Preventing this accumulation by disrupting sphingolipid metabolism via genetic mutation caused a neuroprotective effect on subpopulations of Purkinje cells. Thus, our data indicate that sphingolipid metabolism is involved in the predisposition of neuronal subtypes to neurodegeneration. Patterned degeneration of Purkinje cells (PCs) can be observed in a wide range of neuropathologies, but mechanisms behind nonrandom cerebellar neurodegeneration remain unclear. Sphingolipid metabolism dyshomeostasis typically leads to PC neurodegeneration; hence, we questioned whether local sphingolipid balance underlies regional sensitivity to pathological insults. Here, we investigated the regional compartmentalization of sphingolipids and their related enzymes in the cerebellar cortex in healthy and pathological conditions. Analysis in wild-type animals revealed higher sphingosine kinase 1 (Sphk1) levels in the flocculonodular cerebellum, while sphingosine-1-phosphate (S1P) levels were higher in the anterior cerebellum. Next, we investigated a model for spinocerebellar ataxia type 1 (SCA1) driven by the transgenic expression of the expanded Ataxin 1 protein with 82 glutamine (82Q), exhibiting severe PC degeneration in the anterior cerebellum while the flocculonodular region is preserved. In Atxn1[82Q]/+ mice, we found that levels of Sphk1 and Sphk2 were region-specific decreased and S1P levels increased, particularly in the anterior cerebellum. To determine if there is a causal link between sphingolipid levels and neurodegeneration, we deleted the Sphk1 gene in Atxn1[82Q]/+ mice. Analysis of Atxn1[82Q]/+; Sphk1−/− mice confirmed a neuroprotective effect, rescuing a subset of PCs in the anterior cerebellum, in domains reminiscent of the modules defined by AldolaseC expression. Finally, we showed that Sphk1 deletion acts on the ATXN1[82Q] protein expression and prevents PC degeneration. Taken together, our results demonstrate that there are regional differences in sphingolipid metabolism and that this metabolism is directly involved in PC degeneration in Atxn1[82Q]/+ mice.
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