Assay for the peptide:N-glycanase/NGLY1 and disease-specific biomarkers for diagnosing NGLY1 deficiency

Cytosolic peptide:N-glycanase (NGLY1 in mammals), a highly conserved enzyme in eukaryotes, catalyses the deglycosylation of N-glycans that are attached to glycopeptide/glycoproteins. In 2012, an autosomal recessive disorder related to the NGLY1 gene, which was referred to as NGLY1 deficiency, was reported. Since then, more than 100 patients have been identified. Patients with this disease exhibit various symptoms, including various motor deficits and other neurological problems. Effective therapeutic treatments for this disease, however, have not been established. Most recently, it was demonstrated that the intracerebroventricular administration of an adeno-associated virus 9 vector expressing human NGLY1 during the weaning period allowed some motor functions to be recovered in Ngly1(-/-) rats. This observation led us to hypothesize that a therapeutic intervention for improving these motor deficits or other neurological symptoms found in the patients might be possible. To achieve this, it is critical to establish robust and facile methods for assaying NGLY1 activity in biological samples, for the early diagnosis and evaluation of the therapeutic efficacy for the treatment of NGLY1 deficiency. In this mini review, we summarize progress made in the development of various assay methods for NGLY1 activity, as well as a recent progress in the identification of NGLY1 deficiency-specific biomarkers.

Automated summary

Cytosolic peptide:N-glycanase (NGLY1 in mammals) is a conserved enzyme that plays a role in the deglycosylation of N-glycans attached to glycopeptide/glycoproteins. NGLY1 deficiency is an autosomal recessive disorder related to the NGLY1 gene, characterized by motor deficits and neurological problems. The intracerebroventricular administration of an adeno-associated virus 9 vector expressing human NGLY1 has been shown to partially restore motor functions in Ngly1(-/-) rats, suggesting a possible therapeutic intervention. Therefore, the development of robust assay methods for NGLY1 activity and the identification of NGLY1 deficiency-specific biomarkers are critical for early diagnosis and evaluation of treatment efficacy.