Astrocytic expression of Parkinson's disease-related A53T alpha-synuclein causes neurodegeneration in mice.
Astrocytic expression of Parkinson's disease-related A53T alpha-synuclein causes neurodegeneration in mice.
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DOI：
10.1186/1756-6606-3-12
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发表时间：
2010-04-21
期刊：
影响因子：
3.6
通讯作者：
Cai H
中科院分区：
文献类型：
--
作者：
Gu XL;Long CX;Sun L;Xie C;Lin X;Cai H
帕金森病（PD）是最常见的运动障碍。虽然α-突触核蛋白的神经元沉积是PD和路易体痴呆的病理标志，但α-突触核蛋白阳性蛋白聚集体也存在于星形胶质细胞中。然而，α-突触核蛋白在星形胶质细胞中积聚的病理后果尚不清楚。在这里，我们发现PD相关的A53 T突变体α-突触核蛋白，当选择性地表达在星形胶质细胞中时，诱导小鼠迅速进展的瘫痪。在症状前和有症状的小鼠脑中发现α-突触核蛋白聚集体的积累增加，并与反应性星形胶质细胞增生的扩大相关。星形胶质细胞的正常功能受到损害，如脑微出血和星形胶质细胞谷氨酸转运蛋白下调所证明的，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，其中观察到多巴胺能神经元和运动神经元的显著损失。与小胶质细胞的活化一致，在有症状小鼠的脑中和用来自过表达A53 T α-突触核蛋白的星形胶质细胞的条件培养基处理的培养的小胶质细胞中，环氧化酶1（考克斯-1）的表达水平显著上调。因此，抑制考克斯-1活性延长了突变小鼠的生存期，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。我们的研究结果表明星形胶质细胞α-突触核蛋白在启动神经元的非细胞自主杀伤中起关键作用，表明反应性星形胶质细胞和小胶质细胞作为PD和其他神经退行性疾病的潜在治疗靶点的可行性。
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. 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. 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.
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影响因子：
3.6
作者：
Cullen, Valerie;Lindfors, Maria;Ng, Juliana;Paetau, Anders;Swinton, Erika;Kolodziej, Piotr;Boston, Heather;Saftig, Paul;Woulfe, John;Feany, Mel B.;Myllykangas, Liisa;Schlossmacher, Michael G.;Tyynela, Jaana
通讯作者：
Tyynela, Jaana
DOI：
10.1073/pnas.132197599
发表时间：
2002-06-25
影响因子：
11.1
作者：
Lee, MK;Stirling, W;Price, DL
通讯作者：
Price, DL
影响因子：
6.1
作者：
Chandran, Jayanth S.;Lin, Xian;Cai, Huaibin
通讯作者：
Cai, Huaibin
影响因子：
168.9
作者：
Chartier-Harlin, MC;Kachergus, J;Destée, A
通讯作者：
Destée, A
影响因子：
16.2
作者：
Lin, Xian;Parisiadou, Loukia;Gu, Xing-Long;Wang, Lizhen;Shim, Hoon;Sun, Lixin;Xie, Chengsong;Long, Cai-Xia;Yang, Wan-Jou;Ding, Jinhui;Chen, Zsu Zsu;Gallant, Paul E.;Tao-Cheng, Jung-Hwa;Rudow, Gay;Troncoso, Juan C.;Liu, Zhihua;Li, Zheng;Cai, Huaibin
通讯作者：
Cai, Huaibin