{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T12:43:26Z","timestamp":1792500206601,"version":"4.5.0"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2020,4,7]],"date-time":"2020-04-07T00:00:00Z","timestamp":1586217600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,6,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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\u2212\/\u2212 rats, which showed developmental delay, movement disorder, somatosensory impairment and scoliosis. These phenotypes in Ngly1\u2212\/\u2212 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\u2212\/\u2212 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\u2212\/\u2212 rats. Axonal degradation in the sciatic nerves was also observed, as in human subjects. Ngly1\u2212\/\u2212 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.<\/jats:p>","DOI":"10.1093\/hmg\/ddaa059","type":"journal-article","created":{"date-parts":[[2020,4,3]],"date-time":"2020-04-03T11:08:16Z","timestamp":1585912096000},"page":"1635-1647","source":"Crossref","is-referenced-by-count":59,"title":["Ngly1\n          \u2212\/\u2212 rats develop neurodegenerative phenotypes and pathological abnormalities in their peripheral and central nervous systems"],"prefix":"10.1093","volume":"29","author":[{"given":"Makoto","family":"Asahina","sequence":"first","affiliation":[{"name":"Takeda-CiRA Joint Program (T-CiRA), Kanagawa 2518555, Japan"},{"name":"T-CiRA Discovery, Takeda Pharmaceutical Company Ltd., Kanagawa 2518555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reiko","family":"Fujinawa","sequence":"first","affiliation":[{"name":"Takeda-CiRA Joint Program (T-CiRA), Kanagawa 2518555, Japan"},{"name":"Glycometabolic Biochemistry Laboratory, RIKEN Cluster for Pioneering Research, Saitama 3510198, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sayuri","family":"Nakamura","sequence":"first","affiliation":[{"name":"Nonclinical Safety Research, Axcelead Drug Discovery Partners Inc., Kanagawa 2510012, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kotaro","family":"Yokoyama","sequence":"first","affiliation":[{"name":"Nonclinical Safety Research, Axcelead Drug Discovery Partners Inc., Kanagawa 2510012, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryuichi","family":"Tozawa","sequence":"first","affiliation":[{"name":"Takeda-CiRA Joint Program (T-CiRA), Kanagawa 2518555, Japan"},{"name":"T-CiRA Discovery, Takeda Pharmaceutical Company Ltd., Kanagawa 2518555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadashi","family":"Suzuki","sequence":"first","affiliation":[{"name":"Takeda-CiRA Joint Program (T-CiRA), Kanagawa 2518555, Japan"},{"name":"Glycometabolic Biochemistry Laboratory, RIKEN Cluster for Pioneering Research, Saitama 3510198, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,4,7]]},"reference":[{"key":"2020062904235074900_ref1","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1083\/jcb.149.5.1039","article-title":"PNG1, a yeast gene encoding a highly conserved peptide:N-glycanase","volume":"149","author":"Suzuki","year":"2000","journal-title":"J. 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