Motor Deficit in a Tauopathy Model Is Induced by Disturbances of Axonal Transport Leading to Dying-Back Degeneration and Denentation of Neuromuscular Junctions
Motor Deficit in a Tauopathy Model Is Induced by Disturbances of Axonal Transport Leading to Dying-Back Degeneration and Denentation of Neuromuscular Junctions
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DOI：
10.1016/j.ajpath.2015.06.011
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发表时间：
2015-10-01
影响因子：
6
通讯作者：
Brion, Jean-Pierre
中科院分区：
文献类型：
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作者：
Audouard, Emilie;Van Hees, Laura;Brion, Jean-Pierre
一些神经退行性疾病的特征是认知和运动缺陷，这些缺陷与大脑、脑干和脊髓中 tau 蛋白聚集物的积累相关。 Tg30 小鼠 tau 病模型表达一种人类 tau 蛋白，患有两种与 17 号染色体致病性突变相关的额颞叶痴呆和帕金森病，并在大脑和脊髓中出现严重的运动缺陷和 tau 聚集。为了研究这种运动缺陷的起源，我们分析了 Tg30 小鼠中神经肌肉接头的年龄依赖性神经支配状态和突变 tau 表达。从出生后第 7 天起，在运动神经元、坐骨神经轴突和神经肌肉接头的轴突末端中检测到人类转基因 tau 蛋白。 Tg30 小鼠中神经肌肉接头的发育和成熟并未受到干扰，但成年 Tg30 小鼠中神经肌肉接头的维持受到干扰，导致进行性和严重的肌肉去神经支配。这种肌肉去神经支配与肌肉自发活动的早期电生理迹象和肌肉变性的组织学迹象相关。在运动缺陷之前，轴突末端突触小泡的早期丧失、坐骨神经轴突中 Gallyas 阳性聚集体和组织蛋白酶阳性小泡簇的积累表明，这种去神经支配是由轴突运输紊乱引起的。这种病理生理学机制可能是在某些人类tau蛋白病中观察到的运动体征的原因，以及这些疾病中突触前水平改变导致的突触功能障碍的原因。
Several neurodegenerative diseases are characterized by both cognitive and motor deficits associated with accumulation of tau aggregates in brain, brainstem, and spinal cord. The Tg30 murine tauopathy model expresses a human tau protein bearing two frontotemporal dementia with Parkinsonism linked to chromosome 17 pathogenic mutations and develops a severe motor deficit and tau aggregates in brain and spinal cord. To investigate the origin of this motor deficit, we analyzed the age-dependent innervation status of the neuromuscular junctions and mutant tau expression in Tg30 mice. The human transgenic tau was detected from postnatal day 7 onward in motoneurons, axons in the sciatic nerve, and axon terminals of the neuromuscular junctions. The development and maturation of neuromuscular junctions were not disrupted in Tg30 mice, but their maintenance was disturbed in adult Tg30 mice, resulting in a progressive and severe muscle denervation. This muscle denervation was associated with early electrophysiological signs of muscle spontaneous activities and histological signs of muscle degeneration. Early loss of synaptic vesicles in axon terminals preceding motor deficits, accumulation of Gallyas-positive aggregates, and cathepsin-positive vesicular clusters in axons in the sciatic nerve suggest that this denervation results from disturbances of axonal transport. This physiopathological mechanism might be responsible for motor signs observed in some human tauopathies, and for synaptic dysfunction resulting from alterations at the presynaptic level in these diseases.