# Roles of Glycosylation and Deglycosylation During Animal Development

> **NIH NIH R35** · BAYLOR COLLEGE OF MEDICINE · 2024 · $501,275

## Abstract

The majority of secreted and cell-surface proteins of all cell types studied so far are glycosylated, i.e.
decorated with sugar molecules. Protein glycosylation plays diverse structural and functional roles in
organisms, and is involved in animal development and physiology. Not surprisingly, over 160 human
diseases—collectively called Congenital Disorders of Glycosylation or CDGs—are caused by pathogenic
variants in the glycosylation machinery. Importantly, an approved therapy only exists for ~ 10% of CDGs,
highlighting the need for a better understanding of the mechanisms underlying the phenotypes caused by
glycosylation gene mutations. However, it is difficult to identify the biologically relevant targets and
molecular mechanisms underlying the phenotypes observed upon mutating the genes involved in protein
glycosylation. This is in part due to the diversity of glycan structures attached to proteins and the large number
of proteins decorated by each form of glycosylation. The long-term goals of our research are to understand
how carbohydrate modifications regulate animal development and to use this knowledge to provide insight into
the pathophysiology of human glycosylation disorders, with the hope that these discoveries might help
establish frameworks for novel therapeutic approaches. Support from NIGMS in the last 15 years has allowed
us to provide major insights into the regulation of the Notch signaling pathway by O-glycosylation, identify
recessive POGLUT1 mutations in a novel form of muscular dystrophy (currently supported by NIAMS), and
establish POGLUT1 as a therapeutic target in preclinical models of Alagille syndrome (currently supported by
NIDDK). Moreover, using the Drosophila larval intestine as a model followed by cell culture and mouse
genetic experiments, we have reported evolutionarily conserved roles for a de-glycosylating enzyme called
N-glycanase 1 (NGLY1) in BMP and AMPKα signaling, and have identified BMP4 as a direct target of NGLY1
in flies and mammals. We have also shown that this cytosolic enzyme, which removes N-glycans from
misfolded proteins, plays key roles in gut barrier function, innate immunity, and metabolism in Drosophila.
However, the N-glycoproteins that mediate most NGLY1 loss-of-function phenotypes remain to be identified.
Moreover, in an RNAi screen in Drosophila, we have found that multiple components of the N-glycosylation
machinery have overlapping phenotypes with NGLY1. Building on these recently published and preliminary
data, our focus in the next funding cycle will be on identification of biologically relevant targets of NGLY1
in the above-mentioned processes and elucidation of the developmental functions and critical targets of
glucosidase 1 (GCS1), an evolutionarily conserved enzyme involved in N-glycan trimming in the endoplasmic
reticulum. Successful accomplishment of our studies will establish the common and distinct biological
pathways and N-glycoprotein targets regulated by NGLY1 and other g...

## Key facts

- **NIH application ID:** 10842567
- **Project number:** 2R35GM130317-06
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Hamed Jafar-Nejad
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $501,275
- **Award type:** 2
- **Project period:** 2019-02-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10842567

## Citation

> US National Institutes of Health, RePORTER application 10842567, Roles of Glycosylation and Deglycosylation During Animal Development (2R35GM130317-06). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10842567. Licensed CC0.

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