Patients with mutations in N-glycanase 1 (NGLY1) exhibit a host of developmental abnormalities including a delay in physical and intellectual development, movement disorders, chronic constipation, osteopenia and lack of tears.
NGLY1 is a cytoplasmic deglycosylation enzyme capable of removing N-linked glycans from N-glycoproteins. It has been proposed that upon retrotranslocation of misfolded N-glycoproteins from endoplasmic reticulum (ER) to cytosol, NGLY1 cleaves the N-glycans to facilitate the proteasomal degradation of misfolded proteins. However, the biologically-relevant targets of NGLY1 that contribute to the patient phenotypes and the developmental processes sensitive to loss of its activity in animals are not well understood.
Using Drosophila, we have discovered that NGLY1 (known as Pngl in flies) specifically regulates the bone morphogenetic protein (BMP) signaling during Drosophila intestinal development. In addition, our work suggests that Pngl regulates several other aspects of Drosophila development independently of its role in BMP signaling.
Using a multidisciplinary approach, we are studying the cellular and physiological defects caused by the loss of Pngl in flies. We are also examining whether our findings in flies can shed light on the function of the mammalian NGLY1, with the goal of identifying potential therapeutic targets for the disease.