{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,13]],"date-time":"2026-11-13T15:15:10Z","timestamp":1794582910431,"version":"4.9.1"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T00:00:00Z","timestamp":1771545600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"content-version":"vor","delay-in-days":35,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100012207","name":"Grace Science Foundation","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100012207","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Orphanet J Rare Dis"],"abstract":"Abstract<\/jats:title>\n \n Background<\/jats:title>\n \n N-glycanase 1 (NGLY1) Deficiency is an ultra-rare autosomal recessive disorder of deglycosylation caused by loss-of-function mutations in the\n NGLY1<\/jats:italic>\n gene. Patients present with developmental delay, intellectual disability, hyperkinetic movement disorder, elevated liver enzymes, (hypo)alacrima, and peripheral neuropathy. Despite supportive care, many experience early neurological deterioration, with loss of previously attained motor skills by adolescence. Additionally, life-threatening complications are not uncommon, and the published median lifespan of patients is ~13 years. The pathophysiology of NGLY1 Deficiency remains poorly understood, in part due to limited long-term studies in animal models. Notably,\n Ngly1<\/jats:italic>\n \u207b\n \/<\/jats:sup>\n \u207b mice (C57BL\/6) are embryonically lethal, and prior characterization of\n Ngly1<\/jats:italic>\n \u207b\n \/<\/jats:sup>\n \u207b rats was restricted to young adult rat (~7 months old), leaving late-onset phenotypes and potential lifespan reduction unexplored.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n In the study reported here, longitudinal assessments of phenotypes in\n Ngly1<\/jats:italic>\n \u207b\n \/<\/jats:sup>\n \u207b rats were conducted alongside\n Ngly1<\/jats:italic>\n \u207a\n \/<\/jats:sup>\n \u207b and\n Ngly1<\/jats:italic>\n \u207a\n \/<\/jats:sup>\n \u207a control rats. Survival, motor function, biochemical biomarkers, and brain histopathology were examined in the rats from approximately 6 months to 17\u201318 months of age.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Ngly1<\/jats:italic>\n \u207b\n \/<\/jats:sup>\n \u207b rats exhibited markedly reduced lifespan, progressive neurological decline, and decreased quality of life compared with\n Ngly1<\/jats:italic>\n \u207a\n \/<\/jats:sup>\n \u207b and\n Ngly1<\/jats:italic>\n \u207a\n \/<\/jats:sup>\n \u207a rats. By 9\u201310 months of age, ~50% of the\n Ngly1<\/jats:italic>\n \u207b\n \/<\/jats:sup>\n \u207b rats had either died or met humane euthanasia criteria due to a severe decline in health. Surviving animals displayed phenotypes mirroring human NGLY1 Deficiency disease progression, such as worsening motor deficits (~92% reduction in rotarod latency and ~82% reduction in rearing) and wide-spread neuroinflammation in multiple brain regions. In contrast,\n Ngly1<\/jats:italic>\n \u207a\n \/<\/jats:sup>\n \u207b and\n Ngly1<\/jats:italic>\n \u207a\n \/<\/jats:sup>\n \u207a littermates remained healthy and exhibited normal lifespan and aging profiles. Furthermore, histopathological examination of\n Ngly1<\/jats:italic>\n \u207b\n \/<\/jats:sup>\n \u207b rats identified significant neuropathological abnormalities that were not present in the control cohorts, including loss of peripheral axons and spinal motor neurons.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n The findings reported here demonstrate that\n Ngly1<\/jats:italic>\n \u207b\n \/<\/jats:sup>\n \u207b rats recapitulate the severe, progressive course of NGLY1 Deficiency, including neurodegenerative deterioration, motor deficits, and premature mortality. This extended longitudinal assessment of\n Ngly1<\/jats:italic>\n \u207b\n \/<\/jats:sup>\n \u207b rats provides important insights into disease progression and the shortened lifespan reported for human patients.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1186\/s13023-026-04261-1","type":"journal-article","created":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T19:37:09Z","timestamp":1771616229000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Progressive neurodegeneration, motor decline, and premature mortality in aging Ngly1 deficient rats"],"prefix":"10.1186","volume":"21","author":[{"given":"Lei","family":"Zhu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Selina","family":"Dwight","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9134-7648","authenticated-orcid":false,"given":"William F.","family":"Mueller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Becky","family":"Schweighardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,20]]},"reference":[{"key":"4261_CR1","doi-asserted-by":"crossref","unstructured":"Tadashi Suzuki H, Fujihira. 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