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Reversibility of motor dysfunction in the rat model of NGLY1 deficiency
Molecular Brain ( IF 3.6 ) Pub Date : 2021-06-13 , DOI: 10.1186/s13041-021-00806-6
Makoto Asahina 1, 2 , Reiko Fujinawa 2, 3 , Hiroto Hirayama 2, 3 , Ryuichi Tozawa 1, 2 , Yasushi Kajii 1 , Tadashi Suzuki 2, 3
Affiliation  

N-glycanase 1 (NGLY1) deficiency is a rare inherited disorder characterized by developmental delay, hypolacrima or alacrima, seizure, intellectual disability, motor deficits, and other neurological symptoms. The underlying mechanisms of the NGLY1 phenotype are poorly understood, and no effective therapy is currently available. Similar to human patients, the rat model of NGLY1 deficiency, Ngly1−/−, shows developmental delay, movement disorder, somatosensory impairment, scoliosis, and learning disability. Here we show that single intracerebroventricular administration of AAV9 expressing human NGLY1 cDNA (AAV9-hNGLY1) to Ngly1−/− rats during the weaning period restored NGLY1 expression in the brain and spinal cord, concomitant with increased enzymatic activity of NGLY1 in the brain. hNGLY1 protein expressed by AAV9 was found predominantly in mature neurons, but not in glial cells, of Ngly1−/− rats. Strikingly, intracerebroventricular administration of AAV9-hNGLY1 normalized the motor phenotypes of Ngly1−/− rats assessed by the rota-rod test and gait analysis. The reversibility of motor deficits in Ngly1−/− rats by central nervous system (CNS)-restricted gene delivery suggests that the CNS is the primary therapeutic target organs for NGLY1 deficiency, and that the Ngly1−/− rat model may be useful for evaluating therapeutic treatments in pre-clinical studies.

中文翻译:

NGLY1 缺乏大鼠模型运动功能障碍的可逆性

N-聚糖酶 1 (NGLY1) 缺乏症是一种罕见的遗传性疾病,其特征为发育迟缓、泪液减少或流泪症、癫痫、智力障碍、运动缺陷和其他神经系统症状。NGLY1 表型的潜在机制尚不清楚,目前尚无有效的治疗方法。与人类患者类似,NGLY1 缺乏症 Ngly1−/− 的大鼠模型表现出发育迟缓、运动障碍、体感障碍、脊柱侧弯和学习障碍。在这里,我们发现,在断奶期间,对 Ngly1−/− 大鼠进行单次脑室内注射表达人 NGLY1 cDNA (AAV9-hNGLY1) 的 AAV9,可以恢复大脑和脊髓中的 NGLY1 表达,同时大脑中 NGLY1 的酶活性增加。AAV9 表达的 hNGLY1 蛋白主要存在于 Ngly1−/− 大鼠的成熟神经元中,但不在神经胶质细胞中。引人注目的是,脑室内注射 AAV9-hNGLY1 使通过旋转杆测试和步态分析评估的 Ngly1−/− 大鼠的运动表型正常化。Ngly1−/− 大鼠运动缺陷通过中枢神经系统 (CNS) 限制的基因传递的可逆性表明 CNS 是 NGLY1 缺陷的主要治疗靶器官,并且 Ngly1−/− 大鼠模型可能有助于评估临床前研究中的治疗方法。
更新日期:2021-06-14
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