Abstract
N-glycanase 1 (NGLY1) deficiency is a rare inherited disorder characterized by developmental delay, hypolacrima or alacrima, seizure, intellectual disability, motor deficits, and other neurological symptoms. The underlying mechanisms of the NGLY1 phenotype are poorly understood, and no effective therapy is currently available. Similar to human patients, the rat model of NGLY1 deficiency, Ngly1−/−, shows developmental delay, movement disorder, somatosensory impairment, scoliosis, and learning disability. Here we show that single intracerebroventricular administration of AAV9 expressing human NGLY1 cDNA (AAV9-hNGLY1) to Ngly1−/− rats during the weaning period restored NGLY1 expression in the brain and spinal cord, concomitant with increased enzymatic activity of NGLY1 in the brain. hNGLY1 protein expressed by AAV9 was found predominantly in mature neurons, but not in glial cells, of Ngly1−/− rats. Strikingly, intracerebroventricular administration of AAV9-hNGLY1 normalized the motor phenotypes of Ngly1−/− rats assessed by the rota-rod test and gait analysis. The reversibility of motor deficits in Ngly1−/− rats by central nervous system (CNS)-restricted gene delivery suggests that the CNS is the primary therapeutic target organs for NGLY1 deficiency, and that the Ngly1−/− rat model may be useful for evaluating therapeutic treatments in pre-clinical studies.
Highlights
N-glycanase 1 (NGLY1), known as peptide:N-glycanase, is an evolutionarily conserved enzyme among eukaryotes that plays a crucial role in quality control for newly synthesized N-glycoproteins [1, 2]
We revealed that a single intracerebroventricular administration of AAV9 expressing human NGLY1 cDNA into Ngly1−/− rats restored NGLY1 expression in the central nervous system (CNS), increased the enzymatic activity of NGLY1, and normalized motor function
These results suggest that Ngly1−/− rats are useful for evaluating therapeutic agents and modalities for NGLY1 deficiency in pre-clinical tests
Summary
N-glycanase 1 (NGLY1), known as peptide:N-glycanase, is an evolutionarily conserved enzyme among eukaryotes that plays a crucial role in quality control for newly synthesized N-glycoproteins [1, 2]. N-glycanase 1 (NGLY1) deficiency is a rare inherited disorder that is caused by mutations in the NGLY1 gene. In 2012, the first patient harboring mutations in NGLY1 was identified [3]. More than 60 similar patients have been confirmed worldwide and several clinical reports have been published [4,5,6,7,8,9,10]. NGLY1 deficient patients show a broad spectrum of clinical features including developmental delay, hypolacrima or alacrima, seizure, intellectual disability, and motor deficits [4,5,6,7,8,9,10,11,12,13,14].
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