Behavioral characterization of A53T mice reveals early and late stage deficits related to Parkinson's disease.
Behavioral characterization of A53T mice reveals early and late stage deficits related to Parkinson's disease.
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A53T小鼠的行为表征揭示了与帕金森氏病有关的早期和晚期缺陷。
DOI：
10.1371/journal.pone.0070274
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Dunlop J
中科院分区：
文献类型：
--
作者：
Paumier KL;Sukoff Rizzo SJ;Berger Z;Chen Y;Gonzales C;Kaftan E;Li L;Lotarski S;Monaghan M;Shen W;Stolyar P;Vasilyev D;Zaleska M;D Hirst W;Dunlop J
帕金森病（PD）病理学的特征在于形成称为Lewy小体的神经元内包涵体，其由α-突触核蛋白（α-syn）组成。α-syn基因（A53 T、A30 P和E46 K）的重复、三重或基因突变与常染色体显性遗传PD相关，提示其在PD发病机制中的作用。在PD患者和小鼠模型中，越来越多的证据表明神经元功能障碍发生在蛋白质聚集体的积累之前（即，α-syn）和神经变性。表征症状性功能障碍的时间和性质对于理解α-syn对疾病进展的影响非常重要。此外，这些知识对于确定治疗干预的途径和分子靶点至关重要。为此，我们在与疾病进展相关的特定年龄（2、6和12月龄），检查了表达由小鼠朊病毒启动子指导的人A53 T α-syn变体的转基因小鼠模型中的各种功能和形态学终点。我们的研究结果表明，A53 T小鼠在年龄相关的粗大运动和认知功能障碍发作之前出现精细、感觉运动和突触缺陷。来自旷场和旋转棒测试的结果显示A53 T小鼠在运动活动和减少的焦虑样行为方面发展出年龄依赖性变化。此外，digigait分析显示，这些小鼠在12个月大时会出现异常步态。A53 T小鼠在6个月和12个月时也表现出空间记忆缺陷，如Y-迷宫表现所示。与粗大运动和认知变化相反，A53 T小鼠早在1-2个月大时就在精细运动和感觉运动任务如梳理、筑巢和声惊吓中表现出显著的损伤。这些小鼠在基础突触传递、成对脉冲易化和长时程抑制（LTD）方面也显示出显著的异常。综合起来，这些数据表明A53 T模型表现出与PD患者相似的早发性和迟发性行为和突触损伤，并可能为评估PD的新型治疗干预提供有用的终点。
Parkinson's disease (PD) pathology is characterized by the formation of intra-neuronal inclusions called Lewy bodies, which are comprised of alpha-synuclein (α-syn). Duplication, triplication or genetic mutations in α-syn (A53T, A30P and E46K) are linked to autosomal dominant PD; thus implicating its role in the pathogenesis of PD. In both PD patients and mouse models, there is increasing evidence that neuronal dysfunction occurs before the accumulation of protein aggregates (i.e., α-syn) and neurodegeneration. Characterization of the timing and nature of symptomatic dysfunction is important for understanding the impact of α-syn on disease progression. Furthermore, this knowledge is essential for identifying pathways and molecular targets for therapeutic intervention. To this end, we examined various functional and morphological endpoints in the transgenic mouse model expressing the human A53T α-syn variant directed by the mouse prion promoter at specific ages relating to disease progression (2, 6 and 12 months of age). Our findings indicate A53T mice develop fine, sensorimotor, and synaptic deficits before the onset of age-related gross motor and cognitive dysfunction. Results from open field and rotarod tests show A53T mice develop age-dependent changes in locomotor activity and reduced anxiety-like behavior. Additionally, digigait analysis shows these mice develop an abnormal gait by 12 months of age. A53T mice also exhibit spatial memory deficits at 6 and 12 months, as demonstrated by Y-maze performance. In contrast to gross motor and cognitive changes, A53T mice display significant impairments in fine- and sensorimotor tasks such as grooming, nest building and acoustic startle as early as 1–2 months of age. These mice also show significant abnormalities in basal synaptic transmission, paired-pulse facilitation and long-term depression (LTD). Combined, these data indicate the A53T model exhibits early- and late-onset behavioral and synaptic impairments similar to PD patients and may provide useful endpoints for assessing novel therapeutic interventions for PD.
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影响因子：
168.9
作者：
Chartier-Harlin, MC;Kachergus, J;Destée, A
通讯作者：
Destée, A
影响因子：
16.2
作者：
Giasson, BI;Duda, JE;Lee, VMY
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作者：
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作者：
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作者：
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