Integration and comparison of multi-omics profiles of NGLY1 deficiency plasma and cellular models to identify clinically relevant molecular phenotypes

Abstract

NGLY1 (N-glycanase 1) deficiency is a rare congenital recessive disorder caused by a mutation in the NGLY1 gene, which encodes the cytosol enzyme N-glycanase 1. The NGLY1 protein catalyzes the first step in protein deglycosylation, a process prerequisite for the cytosolic degradation of misfolded glycoproteins. By performing and combining metabolomics and proteomics profiles, we showed that NGLY1 deficiency induced the activation of immune response, disturbed lipid metabolism, biogenic amine synthesis and glutathione metabolism. The discovery was further validated by profiling of patient-derived induced pluripotent stem cells (iPSCs) and differentiated neural progenitor cells (NPCs), which serve as a personalized cellular model of the disease. This study provides new insights into the NGLY1 deficiency pathology and demonstrates that the upregulation of immune response and downregulation of lipid metabolism appear to be important molecular phenotypes of NGLY1 deficiency, together with the dysregulation of amino acid metabolism, biogenic amine synthesis and diverse signaling pathways, likely causing broad downstream syndromes. Collectively, such valuable multi-omics profiles identified broad molecular associations of potential pathological mechanisms during the onset of NGLY1 deficiency and suggested potential therapeutic targets for researchers and clinicians.

NGLY1 mutations cause protein aggregation in human neurons

“…All iPSC lines used in this study were reprogrammed from fibroblasts from three patients carrying homozygous or compound heterozygous loss-of-function alleles of NGLY1 21 ( Figure 1C ) and displaying developmental delay, intellectual disability, a complex hyperkinetic movement disorder, or, in some cases, seizures. 3 Isogenic control lines were created by CRISPR-mediated genome editing to restore one or both deleterious alleles to the corresponding functional allele ( Figure 1C ).…”