Abstract
Mutations in human N-glycanase 1 (NGLY1) cause the first known congenital disorder of deglycosylation (CDDG). Patients with this rare disease, which is also known as NGLY1 deficiency, exhibit global developmental delay and other phenotypes including neuropathy, movement disorder, and constipation. NGLY1 is known to regulate proteasomal and mitophagy gene expression through activation of a transcription factor called "nuclear factor erythroid 2-like 1" (NFE2L1). Loss of NGLY1 has also been shown to impair energy metabolism, but the molecular basis for this phenotype and its in vivo consequences are not well understood. Using a combination of genetic studies, imaging, and biochemical assays, here we report that loss of NGLY1 in the visceral muscle of the Drosophila larval intestine results in a severe reduction in the level of AMP-activated protein kinase α (AMPKα), leading to energy metabolism defects, impaired gut peristalsis, failure to empty the gut, and animal lethality. Ngly1–/– mouse embryonic fibroblasts and NGLY1 deficiency patient fibroblasts also show reduced AMPKα levels. Moreover, pharmacological activation of AMPK signaling significantly suppressed the energy metabolism defects in these cells. Importantly, the reduced AMPKα level and impaired energy metabolism observed in NGLY1 deficiency models are not caused by the loss of NFE2L1 activity. Taken together, these observations identify reduced AMPK signaling as a conserved mediator of energy metabolism defects in NGLY1 deficiency and suggest AMPK signaling as a therapeutic target in this disease.
Highlights
The cytoplasmic enzyme N-glycanase 1 (NGLY1) catalyzes the removal of N-linked glycans from glycoproteins and is thought to operate as part of the endoplasmic reticulum-associated degradation (ERAD) pathway [1]
NGLY1 is responsible for adjusting the activity of proteasome, a cellular machinery involved in protein degradation
NGLY1 has been linked to the function and homeostasis of mitochondria, the major energy production engine in animal cells
Summary
The cytoplasmic enzyme N-glycanase 1 (NGLY1) catalyzes the removal of N-linked glycans from glycoproteins and is thought to operate as part of the endoplasmic reticulum-associated degradation (ERAD) pathway [1]. Recessive mutations in human NGLY1 result in a genetic disorder with various phenotypes including developmental delay, seizures, hypo-/alacrima, elevated liver enzymes, diminished deep tendon reflexes, muscle weakness, orthopedic manifestations, and chronic constipation [2,3,4,5,6,7,8]. This disease is a congenital disorder of deglycosylation (OMIM # 615273) and is commonly referred to as NGLY1 deficiency. Since NRF1 is the official symbol for a distinct protein called nuclear respiratory factor 1 in mammals, we will use NFE2L1 and NFE2L2 in the current work
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