Department of Neurology, College of Medicine, University of Florida, Gainesville, FL 32610-0236, USA.
Hum Mol Genet. 2012 Feb 15;21(4):916-25. doi: 10.1093/hmg/ddr528. Epub 2011 Nov 11.
DYT11 myoclonus-dystonia (M-D) is a movement disorder characterized by myoclonic jerks with dystonic symptoms and caused by mutations in paternally expressed SGCE, which codes for ε-sarcoglycan. Paternally inherited Sgce heterozygous knock-out (KO) mice exhibit motor deficits and spontaneous myoclonus. Abnormal nuclear envelopes have been reported in cellular and mouse models of early-onset DYT1 generalized torsion dystonia; however, the relationship between the abnormal nuclear envelopes and motor symptoms are not clear. Furthermore, it is not known whether abnormal nuclear envelope exists in non-DYT1 dystonia. In the present study, abnormal nuclear envelopes in the striatal medium spiny neurons (MSNs) were found in Sgce KO mice. To analyze whether the loss of ε-sarcoglycan in the striatum alone causes abnormal nuclear envelopes, motor deficits or myoclonus, we produced paternally inherited striatum-specific Sgce conditional KO (Sgce sKO) mice and analyzed their phenotypes. Sgce sKO mice exhibited motor deficits in both beam-walking and accelerated rotarod tests, while they did not exhibit abnormal nuclear envelopes, alteration in locomotion, or myoclonus. The results suggest that the loss of ε-sarcoglycan in the striatum contributes to motor deficits, while it alone does not produce abnormal nuclear envelopes or myoclonus. Development of therapies targeting the striatum to compensate for the loss of ε-sarcoglycan function may rescue the motor deficits in DYT11 M-D patients.
DYT11 肌阵挛 - 肌张力障碍（M-D）是一种运动障碍，其特征是肌阵挛抽搐伴肌张力障碍症状，由父系表达的 SGCE 突变引起，该基因编码 ε- 连接蛋白聚糖。父系遗传的 Sgce 杂合敲除（KO）小鼠表现出运动缺陷和自发性肌阵挛。在早发性 DYT1 全身性扭转痉挛的细胞和小鼠模型中已经报道了异常的核膜；然而，异常核膜与运动症状之间的关系尚不清楚。此外，在非 DYT1 肌张力障碍中是否存在异常核膜尚不清楚。在本研究中，在 Sgce KO 小鼠中发现纹状体中型多棘神经元（MSNs）中的异常核膜。为了分析纹状体中 ε- 连接蛋白聚糖的缺失是否单独导致异常核膜、运动缺陷或肌阵挛，我们产生了父系遗传的纹状体特异性 Sgce 条件性 KO（Sgce sKO）小鼠，并分析了它们的表型。Sgce sKO 小鼠在棒行走和加速旋转棒测试中均表现出运动缺陷，而它们没有表现出异常核膜、运动行为改变或肌阵挛。结果表明，纹状体中 ε- 连接蛋白聚糖的缺失导致运动缺陷，而单独缺失不会产生异常核膜或肌阵挛。针对纹状体开发靶向治疗以补偿 ε- 连接蛋白聚糖功能的缺失可能会挽救 DYT11 M-D 患者的运动缺陷。
