A conserved role for AMP-activated protein kinase in NGLY1 deficiency.

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. N...

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Autores principales:	Seung Yeop Han, Ashutosh Pandey, Tereza Moore, Antonio Galeone, Lita Duraine, Tina M Cowan, Hamed Jafar-Nejad
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2020
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/38ad2190625241eaa6c24799b3b7819a
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spelling	oai:doaj.org-article:38ad2190625241eaa6c24799b3b7819a2021-12-02T20:03:26ZA conserved role for AMP-activated protein kinase in NGLY1 deficiency.1553-73901553-740410.1371/journal.pgen.1009258https://doaj.org/article/38ad2190625241eaa6c24799b3b7819a2020-12-01T00:00:00Zhttps://doi.org/10.1371/journal.pgen.1009258https://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Mutations 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.Seung Yeop HanAshutosh PandeyTereza MooreAntonio GaleoneLita DuraineTina M CowanHamed Jafar-NejadPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 16, Iss 12, p e1009258 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 Seung Yeop Han Ashutosh Pandey Tereza Moore Antonio Galeone Lita Duraine Tina M Cowan Hamed Jafar-Nejad A conserved role for AMP-activated protein kinase in NGLY1 deficiency.
description	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.
format	article
author	Seung Yeop Han Ashutosh Pandey Tereza Moore Antonio Galeone Lita Duraine Tina M Cowan Hamed Jafar-Nejad
author_facet	Seung Yeop Han Ashutosh Pandey Tereza Moore Antonio Galeone Lita Duraine Tina M Cowan Hamed Jafar-Nejad
author_sort	Seung Yeop Han
title	A conserved role for AMP-activated protein kinase in NGLY1 deficiency.
title_short	A conserved role for AMP-activated protein kinase in NGLY1 deficiency.
title_full	A conserved role for AMP-activated protein kinase in NGLY1 deficiency.
title_fullStr	A conserved role for AMP-activated protein kinase in NGLY1 deficiency.
title_full_unstemmed	A conserved role for AMP-activated protein kinase in NGLY1 deficiency.
title_sort	conserved role for amp-activated protein kinase in ngly1 deficiency.
publisher	Public Library of Science (PLoS)
publishDate	2020
url	https://doaj.org/article/38ad2190625241eaa6c24799b3b7819a
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A conserved role for AMP-activated protein kinase in NGLY1 deficiency.

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