Exacerbation of sensorimotor dysfunction in mice deficient in Atp13a2 and overexpressing human wildtype alpha-synuclein.
Exacerbation of sensorimotor dysfunction in mice deficient in Atp13a2 and overexpressing human wildtype alpha-synuclein.
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DOI：
10.1016/j.bbr.2018.01.029
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发表时间：
2018-05-02
影响因子：
2.7
通讯作者：
Fleming SM
中科院分区：
文献类型：
--
作者：
Dirr ER;Ekhator OR;Blackwood R;Holden JG;Masliah E;Schultheis PJ;Fleming SM
ATP13A2基因的功能缺失突变与Kufor-Rakeb综合征和神经元Ceroid脂褐素沉着症有关，前者被指定为帕金森病(PD)的一种遗传型。ATP13A2的功能尚不清楚，但体外研究表明，它是一种溶酶体蛋白，可能与突触前蛋白α-突触核蛋白(ASyn)和某些重金属相互作用。A-Syn的积聚是PD的病理标志--路易小体的主要成分。Atp13a2基因缺陷(13a2)的小鼠会出现年龄依赖性的感觉运动缺陷，并在大脑中积累不溶性的aSyn。为了更好地了解ATP13A2和aSyn之间的相互作用，建立了Atp13a2功能缺失和人野生型aSyn过表达的双突变小鼠。雌性和雄性野生型(WT)、13a2、aSyn和13a2-aSyn小鼠在2、4和6个月大时进行了一系列感觉运动测试，包括粘合剂移除、挑战横梁、自发活动、步态、运动活动和筑巢。双突变小鼠表现出更早的发病和加速的感觉运动功能变化，这些变化与年龄、性别和测试相关。雌性13a2-aSyn小鼠在BEAM和运动活动方面表现出早期和进行性功能障碍。在雄性中，13a2-aSyn小鼠在自发活动和粘连去除方面表现出更严重的损害。ASyn和13a2-aSyn小鼠在横梁、圆柱体和粘合剂去除试验中也观察到性别差异。在其他任务中，双突变小鼠表现出与aSyn小鼠相似的缺陷。这些结果表明，Atp13a2功能的丧失以一种年龄和性别依赖的方式加剧了aSyn小鼠的感觉运动表型。
Loss of function mutations in the gene ATP13A2 are associated with Kufor-Rakeb Syndrome and Neuronal Ceroid Lipofuscinosis, the former designated as an inherited form of Parkinson’s disease (PD). The function of ATP13A2 is unclear but in vitro studies indicate it is a lysosomal protein and may interact with the presynaptic protein alpha-synuclein (aSyn) and certain heavy metals. Accumulation of aSyn is a major component of lewy bodies, the pathological hallmark of PD. Atp13a2-deficient (13a2) mice develop age-dependent sensorimotor deficits, and accumulation of insoluble aSyn in the brain. To better understand the interaction between ATP13A2 and aSyn, double mutant mice with loss of Atp13a2 function combined with overexpression of human wildtype aSyn were generated. Female and male wildtype (WT), 13a2, aSyn, and 13a2-aSyn mice were tested on a battery of sensorimotor tests including adhesive removal, challenging beam traversal, spontaneous activity, gait, locomotor activity, and nest-building at 2, 4, and 6 months of age. Double mutant mice showed an earlier onset and accelerated alterations in sensorimotor function that were age, sex and test-dependent. Female 13a2-aSyn mice showed early and progressive dysfunction on the beam and in locomotor activity. In males, 13a2-aSyn mice showed more severe impairments in spontaneous activity and adhesive removal. Sex differences were also observed in aSyn and 13a2-aSyn mice on the beam, cylinder, and adhesive removal tests. In other tasks, double mutant mice displayed deficits similar to aSyn mice. These results indicate loss of Atp13a2 function exacerbates the sensorimotor phenotype in aSyn mice in an age and sex-dependent manner.
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影响因子：
2.7
作者：
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通讯作者：
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