Impaired axonal transport in motor neurons correlates with clinical prion disease.
Impaired axonal transport in motor neurons correlates with clinical prion disease.
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DOI：
10.1371/journal.ppat.1000558
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发表时间：
2009-08
期刊：
影响因子：
6.7
通讯作者：
Flechsig E
中科院分区：
文献类型：
--
作者：
Ermolayev V;Cathomen T;Merk J;Friedrich M;Härtig W;Harms GS;Klein MA;Flechsig E
朊病毒疾病是致命的神经退行性疾病，可引起运动功能障碍、痴呆和神经病理改变，如海绵状病、星形糖病和神经元丧失。导致临床疾病的一系列事件和不同大脑区域的作用仍然知之甚少。神经系统完整性和轴突特性在朊病毒病理中的作用仍然难以捉摸。目前还没有证据表明功能性轴突损伤与朊病毒疾病有关。我们利用追踪作为轴突运输功能测定与免疫组织化学实验相结合的方法，研究了临床朊病毒病发病时运动神经元的功能性轴突损伤。建立和新颖的共聚焦和超显微技术用于成像和量化标记的神经元。尽管孵育时间有很大差异，但不同小鼠系的红核中有30% ~ 45%的神经元在发病时出现轴突运输损伤，在双侧脑内接种和单侧接种到右侧坐骨神经后。通过替代成像方法分析，高达94%的运动皮层神经元也表现出运输缺陷。我们的数据将不同的朊病毒毒株和接种途径的轴突运输损伤与疾病症状联系起来，并进一步了解了体内朊病毒病理的发展。参与逆行轴突运输的蛋白质定位的改变使我们提出了一种运输中断的机制，该机制涉及rab7介导的货物附着到动力蛋白-动力蛋白途径。这些发现提示了朊病毒疾病早期治疗和诊断方法的新靶点。近一个世纪以来，朊病毒疾病的症状，如痴呆和运动系统缺陷，一直伴随着中枢神经系统的神经病理特征。在过去的几十年里，神经病理变化和临床症状之间的差异表明，引发这种疾病的过程仍然难以捉摸。我们集中于神经系统完整性和轴突特性可能在疾病发展中起重要作用的假设。由于运动系统缺陷是典型的朊病毒病，我们研究了运动系统中心，红核和运动皮质后肢区。尽管脑内朊病毒感染导致双侧红核内标记神经元减少30% - 45%，但感染右侧坐骨神经（后肢主要神经）导致单侧红核内标记神经元减少。后肢运动皮质区神经元减少高达94%。这种减少可能是由运动神经元的功能性轴突损伤引起的。朊病毒诱导的蛋白质分布的改变暗示了货物附着到逆行轴突运输复合体时运输中断的机制。我们的工作揭示了轴突运输损伤与体内疾病症状之间的联系，为朊病毒病理学的发展提供了进一步的见解，并为治疗和诊断方法提供了新的靶点。
Prion diseases are fatal neurodegenerative disorders causing motor dysfunctions, dementia and neuropathological changes such as spongiosis, astroglyosis and neuronal loss. The chain of events leading to the clinical disease and the role of distinct brain areas are still poorly understood. The role of nervous system integrity and axonal properties in prion pathology are still elusive. There is no evidence of both the functional axonal impairments in vivo and their connection with prion disease. We studied the functional axonal impairments in motor neurons at the onset of clinical prion disease using the combination of tracing as a functional assay for axonal transport with immunohistochemistry experiments. Well-established and novel confocal and ultramicroscopy techniques were used to image and quantify labeled neurons. Despite profound differences in the incubation times, 30% to 45% of neurons in the red nucleus of different mouse lines showed axonal transport impairments at the disease onset bilaterally after intracerebral prion inoculation and unilaterally—after inoculation into the right sciatic nerve. Up to 94% of motor cortex neurons also demonstrated transport defects upon analysis by alternative imaging methods. Our data connect axonal transport impairments with disease symptoms for different prion strains and inoculation routes and establish further insight on the development of prion pathology in vivo. The alterations in localization of the proteins involved in the retrograde axonal transport allow us to propose a mechanism of transport disruption, which involves Rab7-mediated cargo attachment to the dynein-dynactin pathway. These findings suggest novel targets for therapeutic and diagnostic approaches in the early stages of prion disease. For almost a century, prion disease symptoms, such as dementia and motor system defects, have been accompanied with neuropathological hallmarks in the central nervous system. In past decades, discrepancies between neuropathological changes and clinical symptoms showed that the processes triggering the disease remain elusive. We concentrated on the hypothesis that nervous system integrity and axonal properties may play an important role in the disease development. Since motor system defects are typical for prion disease, we investigated the centers of the motor system, red nucleus and hindlimb area of motor cortex. Although intracerebral prion infection led to a 30% to 45% bilateral reduction of labeled neurons in the red nucleus, infection into the right sciatic nerve—the major hindlimb nerve—led to unilateral reduction of labeled neurons in the red nucleus. Up to 94% reduction was found in the neurons of motor cortex hindlimb area. This reduction is probably caused by functional axonal impairments in motor neurons. Prion-induced alterations in protein distribution implicate a mechanism of transport disruption at cargo attachment to the retrograde axonal transport complex. Our work reveals a connection between axonal transport impairments and disease symptoms in vivo, providing further insight in the development of prion pathology and suggesting novel targets for therapeutic and diagnostic approaches.
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影响因子：
56.9
作者：
Kaspar, BK;Lladó, J;Gage, FH
通讯作者：
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影响因子：
5.4
作者：
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作者：
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作者：
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DOI：
10.1073/pnas.042678699
发表时间：
2002-02-19
影响因子：
11.1
作者：
Kaspar, BK;Vissel, B;Gage, FH
通讯作者：
Gage, FH