Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice.
Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice.
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DOI：
10.1084/jem.20112457
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发表时间：
2012-05-07
期刊：
影响因子：
--
通讯作者：
Lee VM
中科院分区：
文献类型：
--
作者：
Luk KC;Kehm VM;Zhang B;O'Brien P;Trojanowski JQ;Lee VM
人工合成的a-突触核蛋白原纤维注射到大脑中，扩散远超注射部位，足以加速小鼠帕金森病样病理。错误折叠蛋白的积累是神经退行性疾病的一个基本致病过程。然而，引发α-突触核蛋白（α-Syn）聚集的因素尚不清楚，α-突触核蛋白是神经元内包涵体路易小体（LBs）和路易神经突（LNs）的主要成分，它们是帕金森病（PD）和路易小体痴呆（DLB）的特征。我们在这里发现，在年轻的无症状α-Syn转基因（Tg）小鼠中，脑内注射来自表现α-Syn病理的老年Tg小鼠的脑匀浆加速了细胞内LB/ ln样包涵体的形成和受体动物神经症状的发作。病理性α-Syn沿着主要的中枢神经系统（CNS）途径传播到远远超出注射部位的区域，从而降低了接种动物从注射到死亡的高度可重复性间隔。重要的是，用重组人α-Syn组装的α-Syn淀粉样蛋白原纤维接种可诱导相同的结果。此外，我们首次证明合成α-Syn原纤维完全足以启动pd样lb /LNs并在体内传播疾病。因此，我们的数据表明，在突触核蛋白病中，细胞间的传递和错误折叠α-Syn的传播是LBs/LNs在中枢神经系统扩散的基础。这些发现为了解帕金森病的进展和开发新的治疗方法开辟了新的途径。
Synthetic a-Synuclein fibrils injected into the brain spread far beyond the injection site and are sufficient to accelerate Parkinson’s disease–like pathology in mice. The accumulation of misfolded proteins is a fundamental pathogenic process in neurodegenerative diseases. However, the factors that trigger aggregation of α-Synuclein (α-Syn), the principal component of the intraneuronal inclusions known as Lewy bodies (LBs), and Lewy neurites (LNs), which characterize Parkinson’s disease (PD) and dementia with LBs (DLB), are poorly understood. We show here that in young asymptomatic α-Syn transgenic (Tg) mice, intracerebral injections of brain homogenates derived from older Tg mice exhibiting α-Syn pathology accelerate both the formation of intracellular LB/LN-like inclusions and the onset of neurological symptoms in recipient animals. Pathological α-Syn propagated along major central nervous system (CNS) pathways to regions far beyond injection sites and reduced survival with a highly reproducible interval from injection to death in inoculated animals. Importantly, inoculation with α-Syn amyloid fibrils assembled from recombinant human α-Syn induced identical consequences. Furthermore, we show for the first time that synthetic α-Syn fibrils are wholly sufficient to initiate PD-like LBs/LNs and to transmit disease in vivo. Thus, our data point to a prion-like cascade in synucleinopathies whereby cell–cell transmission and propagation of misfolded α-Syn underlie the CNS spread of LBs/LNs. These findings open up new avenues for understanding the progression of PD and for developing novel therapeutics.
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影响因子：
16.2
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