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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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
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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. |
format | Online Article Text |
id | pubmed-9978932 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
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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