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Generation and characterization of NGLY1 patient-derived midbrain organoids

NGLY1 deficiency is an ultra-rare, autosomal recessive genetic disease caused by mutations in the NGLY1 gene encoding N-glycanase one that removes N-linked glycan. Patients with pathogenic mutations in NGLY1 have complex clinical symptoms including global developmental delay, motor disorder and live...

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Autores principales: Abbott, Joshua, Tambe, Mitali, Pavlinov, Ivan, Farkhondeh, Atena, Nguyen, Ha Nam, Xu, Miao, Pradhan, Manisha, York, Tate, Might, Matthew, Baumgärtel, Karsten, Rodems, Steven, Zheng, Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9978932/
https://www.ncbi.nlm.nih.gov/pubmed/36875753
http://dx.doi.org/10.3389/fcell.2023.1039182
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author Abbott, Joshua
Tambe, Mitali
Pavlinov, Ivan
Farkhondeh, Atena
Nguyen, Ha Nam
Xu, Miao
Pradhan, Manisha
York, Tate
Might, Matthew
Baumgärtel, Karsten
Rodems, Steven
Zheng, Wei
author_facet Abbott, Joshua
Tambe, Mitali
Pavlinov, Ivan
Farkhondeh, Atena
Nguyen, Ha Nam
Xu, Miao
Pradhan, Manisha
York, Tate
Might, Matthew
Baumgärtel, Karsten
Rodems, Steven
Zheng, Wei
author_sort Abbott, Joshua
collection PubMed
description NGLY1 deficiency is an ultra-rare, autosomal recessive genetic disease caused by mutations in the NGLY1 gene encoding N-glycanase one that removes N-linked glycan. Patients with pathogenic mutations in NGLY1 have complex clinical symptoms including global developmental delay, motor disorder and liver dysfunction. To better understand the disease pathogenesis and the neurological symptoms of the NGLY1 deficiency we generated and characterized midbrain organoids using patient-derived iPSCs from two patients with distinct disease-causing mutations–one homozygous for p. Q208X, the other compound heterozygous for p. L318P and p. R390P and CRISPR generated NGLY1 knockout iPSCs. We demonstrate that NGLY1 deficient midbrain organoids show altered neuronal development compared to one wild type (WT) organoid. Both neuronal (TUJ1) and astrocytic glial fibrillary acid protein markers were reduced in NGLY1 patient-derived midbrain organoids along with neurotransmitter GABA. Interestingly, staining for dopaminergic neuronal marker, tyrosine hydroxylase, revealed a significant reduction in patient iPSC derived organoids. These results provide a relevant NGLY1 disease model to investigate disease mechanisms and evaluate therapeutics for treatments of NGLY1 deficiency.
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spelling pubmed-99789322023-03-03 Generation and characterization of NGLY1 patient-derived midbrain organoids Abbott, Joshua Tambe, Mitali Pavlinov, Ivan Farkhondeh, Atena Nguyen, Ha Nam Xu, Miao Pradhan, Manisha York, Tate Might, Matthew Baumgärtel, Karsten Rodems, Steven Zheng, Wei Front Cell Dev Biol Cell and Developmental Biology NGLY1 deficiency is an ultra-rare, autosomal recessive genetic disease caused by mutations in the NGLY1 gene encoding N-glycanase one that removes N-linked glycan. Patients with pathogenic mutations in NGLY1 have complex clinical symptoms including global developmental delay, motor disorder and liver dysfunction. To better understand the disease pathogenesis and the neurological symptoms of the NGLY1 deficiency we generated and characterized midbrain organoids using patient-derived iPSCs from two patients with distinct disease-causing mutations–one homozygous for p. Q208X, the other compound heterozygous for p. L318P and p. R390P and CRISPR generated NGLY1 knockout iPSCs. We demonstrate that NGLY1 deficient midbrain organoids show altered neuronal development compared to one wild type (WT) organoid. Both neuronal (TUJ1) and astrocytic glial fibrillary acid protein markers were reduced in NGLY1 patient-derived midbrain organoids along with neurotransmitter GABA. Interestingly, staining for dopaminergic neuronal marker, tyrosine hydroxylase, revealed a significant reduction in patient iPSC derived organoids. These results provide a relevant NGLY1 disease model to investigate disease mechanisms and evaluate therapeutics for treatments of NGLY1 deficiency. Frontiers Media S.A. 2023-02-16 /pmc/articles/PMC9978932/ /pubmed/36875753 http://dx.doi.org/10.3389/fcell.2023.1039182 Text en Copyright © 2023 Abbott, Tambe, Pavlinov, Farkhondeh, Nguyen, Xu, Pradhan, York, Might, Baumgärtel, Rodems and Zheng. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Abbott, Joshua
Tambe, Mitali
Pavlinov, Ivan
Farkhondeh, Atena
Nguyen, Ha Nam
Xu, Miao
Pradhan, Manisha
York, Tate
Might, Matthew
Baumgärtel, Karsten
Rodems, Steven
Zheng, Wei
Generation and characterization of NGLY1 patient-derived midbrain organoids
title Generation and characterization of NGLY1 patient-derived midbrain organoids
title_full Generation and characterization of NGLY1 patient-derived midbrain organoids
title_fullStr Generation and characterization of NGLY1 patient-derived midbrain organoids
title_full_unstemmed Generation and characterization of NGLY1 patient-derived midbrain organoids
title_short Generation and characterization of NGLY1 patient-derived midbrain organoids
title_sort generation and characterization of ngly1 patient-derived midbrain organoids
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9978932/
https://www.ncbi.nlm.nih.gov/pubmed/36875753
http://dx.doi.org/10.3389/fcell.2023.1039182
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