Early and progressive sensorimotor anomalies in mice overexpressing wild-type human α-synuclein
Early and progressive sensorimotor anomalies in mice overexpressing wild-type human α-synuclein
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DOI：
10.1523/jneurosci.3080-04.2004
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发表时间：
2004-10-20
影响因子：
5.3
通讯作者：
Chesselet, MF
中科院分区：
文献类型：
--
作者：
Fleming, SM;Salcedo, J;Chesselet, MF
α-突触核蛋白在大脑中的积聚是突触核蛋白病的一个标志，突触核蛋白病是包括帕金森病在内的神经退行性疾病。在Thy - 1启动子下过表达α-突触核蛋白的小鼠（ASO小鼠）在大脑皮质和皮质下区域（包括黑质）显示出α-突触核蛋白的异常积聚。我们通过一系列对黑质纹状体多巴胺能系统变化敏感的感觉运动测试来检测ASO小鼠的运动缺陷。雄性野生型和ASO小鼠每2个月进行一次测试，共测试8个月，测试内容包括在具有挑战性的横梁、倒置网格和杆子上的运动表现和协调性，黏附物去除测试中的感觉运动缺陷，圆柱体中的自发活动以及步态。精细运动技能通过从箱子中抓取棉花的能力来评估。ASO小鼠早在2个月大时就表现出运动表现和协调性的显著损伤以及自发活动的减少。运动表现和协调性损伤随着年龄的增长逐渐恶化，并且在6个月时出现感觉运动缺陷。精细运动技能在4个月时发生改变，并在8个月时恶化。这些数据表明，α-突触核蛋白的过表达诱导了一种早期且渐进的行为表型，这种表型可以在多种感觉运动功能测试中被检测到。这些行为缺陷为在突触核蛋白病的遗传模型中评估新型药物治疗提供了一种有用的方法。
Accumulation of alpha-synuclein in brain is a hallmark of synucleinopathies, neurodegenerative diseases that include Parkinson's disease. Mice overexpressing alpha-synuclein under the Thy-1 promoter (ASO) show abnormal accumulation of alpha-synuclein in cortical and subcortical regions of the brain, including the substantia nigra. We examined the motor deficits in ASO mice with a battery of sensorimotor tests that are sensitive to alterations in the nigrostriatal dopaminergic system. Male wild-type and ASO mice were tested every 2 months for 8 months for motor performance and coordination on a challenging beam, inverted grid, and pole, sensorimotor deficits in an adhesive removal test, spontaneous activity in a cylinder, and gait. Fine motor skills were assessed by the ability to grasp cotton from a bin. ASO mice displayed significant impairments in motor performance and coordination and a reduction in spontaneous activity as early as 2 months of age. Motor performance and coordination impairments became progressively worse with age and sensorimotor deficits appeared at 6 months. Fine motor skills were altered at 4 months and worsened at 8 months. These data indicate that overexpression of alpha-synuclein induced an early and progressive behavioral phenotype that can be detected in multiple tests of sensorimotor function. These behavioral deficits provide a useful way to assess novel drug therapy in genetic models of synucleinopathies.