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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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-02-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2023.1039182/full |
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| author | Joshua Abbott Mitali Tambe Ivan Pavlinov Atena Farkhondeh Ha Nam Nguyen Ha Nam Nguyen Miao Xu Manisha Pradhan Tate York Matthew Might Karsten Baumgärtel Steven Rodems Wei Zheng |
| author_facet | Joshua Abbott Mitali Tambe Ivan Pavlinov Atena Farkhondeh Ha Nam Nguyen Ha Nam Nguyen Miao Xu Manisha Pradhan Tate York Matthew Might Karsten Baumgärtel Steven Rodems Wei Zheng |
| author_sort | Joshua Abbott |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-10T09:54:20Z |
| format | Article |
| id | doaj.art-82f3d9bc8e174166b565226d795f1a90 |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-04-10T09:54:20Z |
| publishDate | 2023-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-82f3d9bc8e174166b565226d795f1a902023-02-16T13:07:45ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2023-02-011110.3389/fcell.2023.10391821039182Generation and characterization of NGLY1 patient-derived midbrain organoidsJoshua Abbott0Mitali Tambe1Ivan Pavlinov2Atena Farkhondeh3Ha Nam Nguyen4Ha Nam Nguyen5Miao Xu6Manisha Pradhan7Tate York8Matthew Might9Karsten Baumgärtel10Steven Rodems11Wei Zheng12National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, United StatesNational Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, United StatesNational Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, United StatesNational Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, United StatesInstitute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, United States3Dnamics, Inc., Baltimore, MD, United StatesNational Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, United StatesNational Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, United StatesNeuroScience Associates Inc, Knoxville, TN, United StatesUniversity of Alabama at Birmingham, Birmingham, AL, United StatesTravere Therapeutics, San Diego, CA, United StatesTravere Therapeutics, San Diego, CA, United StatesNational Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, United StatesNGLY1 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.https://www.frontiersin.org/articles/10.3389/fcell.2023.1039182/fullNGLY1midbrain organoidsdopaminergic neuronsGABAGFAP |
| spellingShingle | Joshua Abbott Mitali Tambe Ivan Pavlinov Atena Farkhondeh Ha Nam Nguyen Ha Nam Nguyen Miao Xu Manisha Pradhan Tate York Matthew Might Karsten Baumgärtel Steven Rodems Wei Zheng Generation and characterization of NGLY1 patient-derived midbrain organoids Frontiers in Cell and Developmental Biology NGLY1 midbrain organoids dopaminergic neurons GABA GFAP |
| 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 | NGLY1 midbrain organoids dopaminergic neurons GABA GFAP |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2023.1039182/full |
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