Progressive Neurodegeneration, Motor Decline, and Premature Mortality in Aging Ngly1 Deficient Rats

N-glycanase 1 (NGLY1) Deficiency is an ultra-rare autosomal recessive disorder of deglycosylation caused by loss-of-function mutations in the NGLY1 gene. Patient symptoms are characterized by developmental delay, intellectual disability, hyperkinetic movement disorder, elevated liver enzymes, (hypo)alacrima, and peripheral neuropathy. Despite supportive care, affected individuals often exhibit neurological deterioration at a young age, with caregivers reporting loss of previously attained motor skills by adolescence. Additionally, life-threatening complications are not uncommon, and the published median lifespan of patients is ~ 15 years. The pathophysiology of NGLY1 Deficiency remains poorly understood, in part due to limited long-term studies in animal models. Notably, Ngly1^−/− mice (C57BL/6) are embryonically lethal, and prior characterization of Ngly1^−/− rats was restricted to young adult rat (~ 7 months old) before sacrifice, leaving any late-onset disease phenotypes or understanding of the potential for shortened lifespan unexamined.In the study reported here, longitudinal assessments of phenotypes in Ngly1^−/− rats were conducted alongside Ngly1^+/− and Ngly1^+/+ controls. Survival, motor function, biochemical disease biomarkers, and histopathology of brain tissues were monitored in the rats from approximately 6 months to 17–18 months of age.Results: Ngly1^−/− rats exhibited markedly reduced lifespan and progressive decline in both neurological behavior and quality of life compared with Ngly1^+/− and Ngly1^+/+ rats. By 9–10 months of age, ~ 50% of the Ngly1^−/− rats had either died or met humane euthanasia criteria due to a severe decline in health. Surviving Ngly1^−/− rats showed other phenotypes mirroring human NGLY1 Deficiency disease progression, such as worsening motor deficits and wide-spread neuroinflammation. In contrast, heterozygous and wild-type littermates remained healthy and exhibited normal lifespan and aging profiles. Furthermore, histopathological examination of Ngly1^−/− rats identified significant neuropathological abnormalities not present in the control cohorts, including loss of peripheral axons and spinal motor neurons.Conclusion: The findings reported here demonstrate that Ngly1^−/− rats recapitulate the severe, progressive course of NGLY1 Deficiency, including neurodegenerative deterioration, motor deficits, and premature mortality. This assessment of phenotypes and histology in Ngly1^−/− rats over an extended period of time provides valuable insights with respect to disease progression and lifespan in human patients.