Progressive neurodegeneration, motor decline, and premature mortality in aging Ngly1 deficient rats.

BACKGROUND

N-glycanase 1 (NGLY1) Deficiency is an ultra-rare autosomal recessive disorder of deglycosylation caused by loss-of-function mutations in the NGLY1 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, Ngly1⁻/⁻ mice (C57BL/6) are embryonically lethal, and prior characterization of Ngly1⁻/⁻ rats was restricted to young adult rat (~7 months old), leaving late-onset phenotypes and potential lifespan reduction unexplored.

METHODS

In the study reported here, longitudinal assessments of phenotypes in Ngly1⁻/⁻ rats were conducted alongside Ngly1⁺/⁻ and Ngly1⁺/⁺ control rats. Survival, motor function, biochemical biomarkers, and brain histopathology were examined in the rats from approximately 6 months to 17–18 months of age.

RESULTS

Ngly1⁻/⁻ rats exhibited markedly reduced lifespan, progressive neurological decline, and decreased 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 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, Ngly1⁺/⁻ and Ngly1⁺/⁺ littermates remained healthy and exhibited normal lifespan and aging profiles. Furthermore, histopathological examination of Ngly1⁻/⁻ rats identified significant neuropathological abnormalities that were 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 extended longitudinal assessment of Ngly1⁻/⁻ rats provides important insights into disease progression and the shortened lifespan reported for human patients.