Dirr Emily R, Ekhator Osunde R, Blackwood Rachel, Holden John G, Masliah Eliezer, Schultheis Patrick J, Fleming Sheila M
Department of Neurology, School of Medicine, University of Cincinnati, USA.
University of California San Diego, La Jolla, CA, USA.
Behav Brain Res. 2018 May 2;343:41-49. doi: 10.1016/j.bbr.2018.01.029. Epub 2018 Feb 3.
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.
基因ATP13A2的功能缺失突变与库福-拉凯布综合征和神经元蜡样脂褐质沉积症相关，前者被认定为帕金森病（PD）的一种遗传形式。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）及某些重金属相互作用。aSyn的积聚是路易小体的主要成分，而路易小体是PD的病理标志。Atp13a2基因缺陷（13a2）小鼠会出现年龄依赖性的感觉运动功能障碍，且大脑中会积累不溶性aSyn。为了更好地理解ATP13A2与aSyn之间的相互作用，研究人员构建了Atp13a2功能缺失与人类野生型aSyn过表达相结合的双突变小鼠。对雌性和雄性野生型（WT）、13a2、aSyn及13a2-aSyn小鼠在2、4和6月龄时进行了一系列感觉运动测试，包括去除黏附物、挑战性横梁穿越、自发活动、步态、运动活动及筑巢测试。双突变小鼠表现出感觉运动功能的发病更早且变化加速，这些变化具有年龄、性别和测试依赖性。雌性13a2-aSyn小鼠在横梁和运动活动方面表现出早期且进行性的功能障碍。在雄性中，13a2-aSyn小鼠在自发活动和去除黏附物方面表现出更严重的损伤。在横梁、圆柱体和去除黏附物测试中，aSyn和13a2-aSyn小鼠也观察到了性别差异。在其他任务中，双突变小鼠表现出与aSyn小鼠类似的缺陷。这些结果表明，Atp13a2功能缺失以年龄和性别依赖性方式加剧了aSyn小鼠的感觉运动表型。
