N-glycanase 1 (NGLY1) deficiency, an autosomal recessive disease caused by mutations in the NGLY1 gene, is characterized by developmental delay, hypolacrima or alacrima, seizure, intellectual disability, movement disorders and other neurological phenotypes. Because of few animal models that recapitulate these clinical signatures, the mechanisms of the onset of the disease and its progression are poorly understood, and the development of therapies is hindered. In this study, we generated the systemic Ngly1-deficient rodent model, Ngly1^−/− rats, which showed developmental delay, movement disorder, somatosensory impairment and scoliosis. These phenotypes in Ngly1^−/− rats are consistent with symptoms in human patients. In accordance with the pivotal role played by NGLY1 in endoplasmic reticulum-associated degradation processes, cleaving N-glycans from misfolded glycoproteins in the cytosol before they can be degraded by the proteasome, loss of Ngly1 led to accumulation of cytoplasmic ubiquitinated proteins, a marker of misfolded proteins in the neurons of the central nervous system of Ngly1^−/− rats. Histological analysis identified prominent pathological abnormalities, including necrotic lesions, mineralization, intra- and extracellular eosinophilic bodies, astrogliosis, microgliosis and significant loss of mature neurons in the thalamic lateral and the medial parts of the ventral posterior nucleus and ventral lateral nucleus of Ngly1^−/− rats. Axonal degradation in the sciatic nerves was also observed, as in human subjects. Ngly1^−/− rats, which mimic the symptoms of human patients, will be a useful animal model for preclinical testing of therapeutic options and understanding the detailed mechanisms of NGLY1 deficiency.

中文翻译：

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Ngly1 -/- 大鼠的外周和中枢神经系统出现神经退行性表型和病理异常。

N-聚糖酶 1 (NGLY1) 缺乏症是一种由NGLY1基因突变引起的常染色体隐性遗传病，其特征是发育迟缓、低泪或流泪、癫痫、智力障碍、运动障碍和其他神经系统表型。由于很少有动物模型能够重现这些临床特征，因此对该疾病的发病机制及其进展知之甚少，并且阻碍了疗法的发展。在本研究中，我们生成了全身性Ngly1 缺陷型啮齿动物模型Ngly1 ^-/-大鼠，其表现出发育迟缓、运动障碍、躯体感觉障碍和脊柱侧弯。Ngly1 中的这些表型^-/-大鼠与人类患者的症状一致。根据 NGLY1 在内质网相关降解过程中发挥的关键作用，将 N-聚糖从胞质溶胶中错误折叠的糖蛋白中切割出来，然后才能被蛋白酶体降解，Ngly1 的缺失导致细胞质泛素化蛋白的积累，这是Ngly1 ^-/-大鼠中枢神经系统神经元中错误折叠的蛋白质。组织学分析确定了显着的病理异常，包括坏死性病变、矿化、细胞内外嗜酸性粒细胞增多、星形胶质细胞增生、小胶质细胞增生以及丘脑外侧和腹侧后核的内侧部分以及腹外侧核的成熟神经元的显着丧失。Ngly1 ^-/-大鼠。与人类受试者一样，还观察到坐骨神经中的轴突退化。Ngly1 ^-/-大鼠模仿人类患者的症状，将成为一种有用的动物模型，可用于治疗选择的临床前测试和了解 NGLY1 缺乏症的详细机制。