• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Molecular brain >Astrocytic expression of Parkinson's disease-related A53T α-synuclein causes neurodegeneration in mice
【24h】

Astrocytic expression of Parkinson's disease-related A53T α-synuclein causes neurodegeneration in mice

机译：帕金森氏病相关的A53Tα-突触核蛋白的星形胶质细胞表达引起小鼠神经退行性变

获取原文
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Background Parkinson's disease (PD) is the most common movement disorder. While neuronal deposition of α-synuclein serves as a pathological hallmark of PD and Dementia with Lewy Bodies, α-synuclein-positive protein aggregates are also present in astrocytes. The pathological consequence of astrocytic accumulation of α-synuclein, however, is unclear. Results Here we show that PD-related A53T mutant α-synuclein, when selectively expressed in astrocytes, induced rapidly progressed paralysis in mice. Increasing accumulation of α-synuclein aggregates was found in presymptomatic and symptomatic mouse brains and correlated with the expansion of reactive astrogliosis. The normal function of astrocytes was compromised as evidenced by cerebral microhemorrhage and down-regulation of astrocytic glutamate transporters, which also led to increased inflammatory responses and microglial activation. Interestingly, the activation of microglia was mainly detected in the midbrain, brainstem and spinal cord, where a significant loss of dopaminergic and motor neurons was observed. Consistent with the activation of microglia, the expression level of cyclooxygenase 1 (COX-1) was significantly up-regulated in the brain of symptomatic mice and in cultured microglia treated with conditioned medium derived from astrocytes over-expressing A53T α-synuclein. Consequently, the suppression of COX-1 activities extended the survival of mutant mice, suggesting that excess inflammatory responses elicited by reactive astrocytes may contribute to the degeneration of neurons. Conclusions Our findings demonstrate a critical involvement of astrocytic α-synuclein in initiating the non-cell autonomous killing of neurons, suggesting the viability of reactive astrocytes and microglia as potential therapeutic targets for PD and other neurodegenerative diseases.
机译：背景帕金森氏病（PD）是最常见的运动障碍。尽管α-突触核蛋白的神经元沉积是PD和痴呆伴路易体的病理标志，但星形胶质细胞中也存在α-突触核蛋白阳性蛋白聚集体。然而，尚不清楚α-突触核蛋白的星形细胞积累的病理结果。结果在这里，我们显示PD相关的A53T突变体α-突触核蛋白在星形胶质细胞中选择性表达时，在小鼠中引起快速进展的瘫痪。在症状前和有症状的小鼠大脑中发现α-突触核蛋白聚集体的积累增加，并且与反应性星形胶质增生的扩大有关。脑微出血和星形细胞谷氨酸转运蛋白的下调证明了星形胶质细胞的正常功能受损，这也导致炎症反应和小胶质细胞活化增加。有趣的是，小胶质细胞的激活主要在中脑，脑干和脊髓中检测到，在那里观察到多巴胺能和运动神经元的大量损失。与小胶质细胞的激活一致，有症状小鼠的大脑和用过表达A53Tα-突触核蛋白的星形胶质细胞衍生的条件培养基处理的小胶质细胞中环氧合酶1（COX-1）的表达水平显着上调。因此，COX-1活性的抑制延长了突变小鼠的存活，表明反应性星形胶质细胞引起的过度炎症反应可能有助于神经元的变性。结论我们的发现表明，星形胶质细胞α-突触核蛋白在启动神经元的非细胞自发杀伤过程中起关键作用，提示反应性星形胶质细胞和小胶质细胞的活力是PD和其他神经退行性疾病的潜在治疗靶标。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号