Dopamine D2 receptor signaling modulates mutant ataxin-1 S776 phosphorylation and aggregation
Dopamine D2 receptor signaling modulates mutant ataxin-1 S776 phosphorylation and aggregation
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DOI：
10.1111/j.1471-4159.2010.06791.x
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发表时间：
2010-08-01
影响因子：
4.7
通讯作者：
Vig, Parminder J. S.
中科院分区：
文献类型：
--
作者：
Hearst, Scoty M.;Lopez, Mariper E.;Vig, Parminder J. S.
脊髓小脑性共济失调1（SCA 1）是一种显性遗传性神经退行性疾病，与小脑浦肯野细胞（PC）和脑干神经元缺失导致的进行性共济失调相关。在SCA 1转基因小鼠的PC中，引起疾病的共济失调蛋白-1介导含有S100 B的细胞质空泡的形成，并进一步自聚集形成核内包涵体。ataxin-1蛋白的确切功能尚未完全了解。然而，突变型共济失调蛋白-1蛋白的聚集和神经毒性依赖于丝氨酸776（S776）处的磷酸化。尽管蛋白激酶A（PKA）与S776激酶有关联，但SCA 1中PKA/共济失调蛋白-1调节的机制仍不清楚。我们认为多巴胺D-2受体（D2 R）/S100 B通路可能参与调节PCs中PKA活性。使用用GFP-共济失调蛋白-1 [82 Q]瞬时转染的D2 R/S100 B HEK稳定细胞系，我们证明D2 R/S100 B途径的刺激引起突变型共济失调蛋白-1 S776磷酸化和共济失调蛋白-1聚集的减少。通过毛喉素激活PKA导致增强的S776磷酸化和增加共济失调蛋白-1核聚集，这被D2 R激动剂溴隐亭和PKA抑制剂H89治疗抑制。此外，治疗SCA 1转基因PC切片培养物与毛喉素诱导PC树突与体内观察到的神经退行性形态异常。综上所述，我们的数据支持PKA依赖性突变型共济失调蛋白-1磷酸化和聚集可以通过D2 R/S100 B信号转导调节的机制。
P>Spinocerebellar ataxia 1 (SCA1) is a dominantly inherited neurodegenerative disease associated with progressive ataxia resulting from the loss of cerebellar Purkinje cells (PCs) and neurons in the brainstem. In PCs of SCA1 transgenic mice, the disease causing ataxin-1 protein mediates the formation of S100B containing cytoplasmic vacuoles and further self-aggregates to form intranuclear inclusions. The exact function of the ataxin-1 protein is not fully understood. However, the aggregation and neurotoxicity of the mutant ataxin-1 protein is dependent on the phosphorylation at serine 776 (S776). Although protein kinase A (PKA) has been implicated as the S776 kinase, the mechanism of PKA/ataxin-1 regulation in SCA1 is still not clear. We propose that a dopamine D-2 receptor (D2R)/S100B pathway may be involved in modulating PKA activity in PCs. Using a D2R/S100B HEK stable cell line transiently transfected with GFP-ataxin-1[82Q], we demonstrate that stimulation of the D2R/S100B pathway caused a reduction in mutant ataxin-1 S776 phosphorylation and ataxin-1 aggregation. Activation of PKA by forskolin resulted in an enhanced S776 phosphorylation and increased ataxin-1 nuclear aggregation, which was suppressed by treatment with D2R agonist bromocriptine and PKA inhibitor H89. Furthermore, treating SCA1 transgenic PC slice cultures with forskolin induced neurodegenerative morphological abnormalities in PC dendrites consistent with those observed in vivo. Taken together our data support a mechanism where PKA dependent mutant ataxin-1 phosphorylation and aggregation can be regulated by D2R/S100B signaling.