Department of Neurology, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
Behav Brain Res. 2012 Feb 1;227(1):12-20. doi: 10.1016/j.bbr.2011.10.024. Epub 2011 Oct 21.
Myoclonus-dystonia (M-D) is a movement disorder characterized by myoclonic jerks with dystonia. DYT11 M-D is caused by mutations in SGCE which codes for ɛ-sarcoglycan. SGCE is maternally imprinted and paternally expressed. Abnormal nuclear envelope has been reported in mouse models of DYT1 generalized torsion dystonia. However, it is not known whether similar alterations occur in DYT11 M-D. We developed a mouse model of DYT11 M-D using paternally inherited Sgce heterozygous knockout (Sgce KO) mice and reported that they had myoclonus and motor coordination and learning deficits in the beam-walking test. However, the specific brain regions that contribute to these phenotypes have not been identified. Since ɛ-sarcoglycan is highly expressed in the cerebellar Purkinje cells, here we examined the nuclear envelope in these cells using a transmission electron microscope and found that they are abnormal in Sgce KO mice. Our results put DYT11 M-D in a growing family of nuclear envelopathies. To analyze the effect of loss of ɛ-sarcoglycan function in the cerebellar Purkinje cells, we produced paternally inherited cerebellar Purkinje cell-specific Sgce conditional knockout (Sgce pKO) mice. Sgce pKO mice showed motor learning deficits, while they did not show abnormal nuclear envelope in the cerebellar Purkinje cells, robust motor deficits, or myoclonus. The results suggest that ɛ-sarcoglycan in the cerebellar Purkinje cells contributes to the motor learning, while loss of ɛ-sarcoglycan in other brain regions may contribute to nuclear envelope abnormality, myoclonus and motor coordination deficits.
肌阵挛-肌张力障碍（M-D）是一种以肌阵挛性抽搐伴肌张力障碍为特征的运动障碍。DYT11 M-D 是由 SGCE 基因突变引起的，该基因编码ɛ-肌聚糖。SGCE 呈母系印迹，父系表达。在 DYT1 全身性扭转痉挛的小鼠模型中已报道存在异常核膜。然而，DYT11 M-D 是否存在类似的改变尚不清楚。我们使用父系遗传的 Sgce 杂合子敲除（Sgce KO）小鼠建立了 DYT11 M-D 小鼠模型，并报道它们在走棒试验中出现肌阵挛和运动协调及学习缺陷。然而，导致这些表型的特定脑区尚未确定。由于ɛ-肌聚糖在小脑浦肯野细胞中高度表达，我们在这里使用透射电子显微镜检查这些细胞的核膜，发现 Sgce KO 小鼠的核膜异常。我们的结果将 DYT11 M-D 归入不断扩大的核膜病家族。为了分析小脑浦肯野细胞中丧失ɛ-肌聚糖功能的影响，我们产生了父系遗传的小脑浦肯野细胞特异性 Sgce 条件性敲除（Sgce pKO）小鼠。Sgce pKO 小鼠表现出运动学习缺陷，但小脑浦肯野细胞中未见异常核膜、严重运动缺陷或肌阵挛。结果表明，小脑浦肯野细胞中的ɛ-肌聚糖有助于运动学习，而其他脑区丧失ɛ-肌聚糖可能导致核膜异常、肌阵挛和运动协调缺陷。
