Xing Hong, Girdhar Pallavi, Yokoi Fumiaki, Li Yuqing
Norman Fixel Institute of Neurological Diseases, McKnight Brain Institute, and Department of Neurology, College of Medicine, University of Florida, Gainesville, FL 32610-0236, USA.
Dystonia. 2025;4. doi: 10.3389/dyst.2025.14415. Epub 2025 Mar 18.
Myoclonus is a hyperkinetic movement disorder characterized by sudden, brief, involuntary jerks of single or multiple muscles. Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Myoclonus-dystonia (M-D) or DYT11 dystonia is an early-onset genetic disorder characterized by subcortical myoclonus and less pronounced dystonia. DYT11 dystonia is the primary genetic M-D caused by loss of function mutations in , which codes for ε-sarcoglycan. knockout (KO) mice model DYT11 dystonia and exhibit myoclonus, motor deficits, and psychiatric-like behaviors. Neuroimaging studies show abnormal cerebellar activity in DYT11 dystonia patients. Acute small hairpin RNA (shRNA) knockdown of mRNA in the adult cerebellum leads to motor deficits, myoclonic-like jerky movements, and altered Purkinje cell firing. Whether KO mice show similar abnormal Purkinje cell firing as the acute shRNA knockdown mice is unknown. We used acute cerebellar slice recording in KO mice to address this issue. The Purkinje cells from KO mice showed spontaneous and intrinsic excitability changes compared to the wild-type (WT) mice. Intrinsic membrane properties were not altered. The female KO mice had more profound alterations in Purkinje cell firing than males, which may correspond to the early onset of the symptoms in female human patients and more pronounced myoclonus in female KO mice. Our results suggest that the abnormal Purkinje cell firing in the KO mice contributes to the manifestation of the myoclonus and other motor symptoms in DYT11 dystonia patients.
肌阵挛是一种运动亢进性运动障碍，其特征为单个或多个肌肉突然、短暂、不自主的抽搐。肌张力障碍是一种运动障碍，其特征为持续或间歇性的肌肉收缩，导致异常的、通常是重复性的运动、姿势或两者兼有。肌阵挛性肌张力障碍（M-D）或DYT11肌张力障碍是一种早发性遗传疾病，其特征为皮质下肌阵挛和不太明显的肌张力障碍。DYT11肌张力障碍是由编码ε-肌聚糖的功能丧失突变引起的原发性遗传性M-D。ε-肌聚糖基因敲除（KO）小鼠可模拟DYT11肌张力障碍，并表现出肌阵挛、运动缺陷和类似精神疾病的行为。神经影像学研究显示，DYT11肌张力障碍患者的小脑活动异常。在成年小鼠小脑中急性敲低ε-肌聚糖基因的mRNA会导致运动缺陷、肌阵挛样抽搐运动以及浦肯野细胞放电改变。ε-肌聚糖基因敲除小鼠是否表现出与急性短发夹RNA（shRNA）敲低小鼠类似的浦肯野细胞放电异常尚不清楚。我们使用ε-肌聚糖基因敲除小鼠的急性小脑切片记录来解决这个问题。与野生型（WT）小鼠相比，ε-肌聚糖基因敲除小鼠的浦肯野细胞表现出自发性和内在兴奋性变化。内在膜特性未改变。雌性ε-肌聚糖基因敲除小鼠的浦肯野细胞放电改变比雄性更明显，这可能与女性人类患者症状的早发以及雌性ε-肌聚糖基因敲除小鼠更明显的肌阵挛相对应。我们的结果表明，ε-肌聚糖基因敲除小鼠中浦肯野细胞放电异常导致了DYT11肌张力障碍患者肌阵挛和其他运动症状的表现。
