Selective molecular alterations in the autophagy pathway in patients with Lewy body disease and in models of alpha-synucleinopathy.
Selective molecular alterations in the autophagy pathway in patients with Lewy body disease and in models of alpha-synucleinopathy.
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DOI：
10.1371/journal.pone.0009313
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发表时间：
2010-02-19
期刊：
影响因子：
3.7
通讯作者：
Masliah E
中科院分区：
文献类型：
--
作者：
Crews L;Spencer B;Desplats P;Patrick C;Paulino A;Rockenstein E;Hansen L;Adame A;Galasko D;Masliah E
路易体病是一组异质性神经退行性疾病，特征为α-突触核蛋白蓄积，包括路易体痴呆（DLB）和帕金森病（PD）。最近的证据表明，参与α-突触核蛋白清除的溶酶体途径（即自噬）的损伤可能发挥重要作用。出于这个原因，我们试图检查自噬途径成员在DLB和阿尔茨海默病（AD）患者脑中以及α-突触核蛋白转基因小鼠中的表达水平。通过免疫印迹分析，与对照组和AD相比，在DLB病例中，mTor水平升高，Atg 7水平降低。与对照组相比，DLB中自噬途径的其他组分如Atg 5、Atg 10、Atg 12和Beclin-1的水平没有差异。在DLB脑中，mTor在显示α-突触核蛋白积聚的神经元中更丰富。这些神经元也表现出异常表达的溶酶体标志物，如LC 3，和超微结构分析揭示了丰富的和异常的自噬体的存在。在α-突触核蛋白转基因小鼠的大脑中观察到类似的变化。脑内输注雷帕霉素（一种mTor抑制剂）或注射表达Atg 7的慢病毒载体可减少转基因小鼠中α-突触核蛋白的蓄积，并改善相关的神经退行性改变。这项研究支持了自噬途径中的缺陷，更具体地说，mTor和Atg 7中的缺陷与DLB病例和α-突触核蛋白转基因模型中的神经变性相关的观点，并支持了自噬途径调节剂可能具有潜在治疗作用的可能性。
Lewy body disease is a heterogeneous group of neurodegenerative disorders characterized by α-synuclein accumulation that includes dementia with Lewy bodies (DLB) and Parkinson's Disease (PD). Recent evidence suggests that impairment of lysosomal pathways (i.e. autophagy) involved in α-synuclein clearance might play an important role. For this reason, we sought to examine the expression levels of members of the autophagy pathway in brains of patients with DLB and Alzheimer's Disease (AD) and in α-synuclein transgenic mice. By immunoblot analysis, compared to controls and AD, in DLB cases levels of mTor were elevated and Atg7 were reduced. Levels of other components of the autophagy pathway such as Atg5, Atg10, Atg12 and Beclin-1 were not different in DLB compared to controls. In DLB brains, mTor was more abundant in neurons displaying α-synuclein accumulation. These neurons also showed abnormal expression of lysosomal markers such as LC3, and ultrastructural analysis revealed the presence of abundant and abnormal autophagosomes. Similar alterations were observed in the brains of α-synuclein transgenic mice. Intra-cerebral infusion of rapamycin, an inhibitor of mTor, or injection of a lentiviral vector expressing Atg7 resulted in reduced accumulation of α-synuclein in transgenic mice and amelioration of associated neurodegenerative alterations. This study supports the notion that defects in the autophagy pathway and more specifically in mTor and Atg7 are associated with neurodegeneration in DLB cases and α-synuclein transgenic models and supports the possibility that modulators of the autophagy pathway might have potential therapeutic effects.
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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
神经元中的自噬诱导和自噬体清除：与阿尔茨海默氏病自噬病理学的关系。
影响因子：
5.3
作者：
Boland, Barry;Kumar, Asok;Lee, Sooyeon;Platt, Frances M.;Wegiel, Jerzy;Yu, W. Haung;Nixon, Ralph A.
通讯作者：
Nixon, Ralph A.
影响因子：
6.1
作者：
Chu, Yaping;Dodiya, Hemraj;Kordower, Jeffrey H.
通讯作者：
Kordower, Jeffrey H.
影响因子：
12.7
作者：
Jellinger, Kurt A.;Attems, Johannes
通讯作者：
Attems, Johannes
影响因子：
2.5
作者：
HANSEN, LA;MASLIAH, E;REXIN, D
通讯作者：
REXIN, D