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Human SPG11 cerebral organoids reveal cortical neurogenesis impairment

Spastic paraplegia gene 11(SPG11)-linked hereditary spastic paraplegia is a complex monogenic neurodegenerative disease that in addition to spastic paraplegia is characterized by childhood onset cognitive impairment, thin corpus callosum and enlarged ventricles. We have previously shown impaired pro...

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Autores principales: Pérez-Brangulí, Francesc, Buchsbaum, Isabel Y, Pozner, Tatyana, Regensburger, Martin, Fan, Wenqiang, Schray, Annika, Börstler, Tom, Mishra, Himanshu, Gräf, Daniela, Kohl, Zacharias, Winkler, Jürgen, Berninger, Benedikt, Cappello, Silvia, Winner, Beate
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400051/
https://www.ncbi.nlm.nih.gov/pubmed/30476097
http://dx.doi.org/10.1093/hmg/ddy397
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author Pérez-Brangulí, Francesc
Buchsbaum, Isabel Y
Pozner, Tatyana
Regensburger, Martin
Fan, Wenqiang
Schray, Annika
Börstler, Tom
Mishra, Himanshu
Gräf, Daniela
Kohl, Zacharias
Winkler, Jürgen
Berninger, Benedikt
Cappello, Silvia
Winner, Beate
author_facet Pérez-Brangulí, Francesc
Buchsbaum, Isabel Y
Pozner, Tatyana
Regensburger, Martin
Fan, Wenqiang
Schray, Annika
Börstler, Tom
Mishra, Himanshu
Gräf, Daniela
Kohl, Zacharias
Winkler, Jürgen
Berninger, Benedikt
Cappello, Silvia
Winner, Beate
author_sort Pérez-Brangulí, Francesc
collection PubMed
description Spastic paraplegia gene 11(SPG11)-linked hereditary spastic paraplegia is a complex monogenic neurodegenerative disease that in addition to spastic paraplegia is characterized by childhood onset cognitive impairment, thin corpus callosum and enlarged ventricles. We have previously shown impaired proliferation of SPG11 neural progenitor cells (NPCs). For the delineation of potential defect in SPG11 brain development we employ 2D culture systems and 3D human brain organoids derived from SPG11 patients’ iPSC and controls. We reveal that an increased rate of asymmetric divisions of NPCs leads to proliferation defect, causing premature neurogenesis. Correspondingly, SPG11 organoids appeared smaller than controls and had larger ventricles as well as thinner germinal wall. Premature neurogenesis and organoid size were rescued by GSK3 inhibititors including the Food and Drug Administration-approved tideglusib. These findings shed light on the neurodevelopmental mechanisms underlying disease pathology.
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spelling pubmed-64000512019-03-12 Human SPG11 cerebral organoids reveal cortical neurogenesis impairment Pérez-Brangulí, Francesc Buchsbaum, Isabel Y Pozner, Tatyana Regensburger, Martin Fan, Wenqiang Schray, Annika Börstler, Tom Mishra, Himanshu Gräf, Daniela Kohl, Zacharias Winkler, Jürgen Berninger, Benedikt Cappello, Silvia Winner, Beate Hum Mol Genet General Article Spastic paraplegia gene 11(SPG11)-linked hereditary spastic paraplegia is a complex monogenic neurodegenerative disease that in addition to spastic paraplegia is characterized by childhood onset cognitive impairment, thin corpus callosum and enlarged ventricles. We have previously shown impaired proliferation of SPG11 neural progenitor cells (NPCs). For the delineation of potential defect in SPG11 brain development we employ 2D culture systems and 3D human brain organoids derived from SPG11 patients’ iPSC and controls. We reveal that an increased rate of asymmetric divisions of NPCs leads to proliferation defect, causing premature neurogenesis. Correspondingly, SPG11 organoids appeared smaller than controls and had larger ventricles as well as thinner germinal wall. Premature neurogenesis and organoid size were rescued by GSK3 inhibititors including the Food and Drug Administration-approved tideglusib. These findings shed light on the neurodevelopmental mechanisms underlying disease pathology. Oxford University Press 2019-03-15 2018-11-22 /pmc/articles/PMC6400051/ /pubmed/30476097 http://dx.doi.org/10.1093/hmg/ddy397 Text en © The Author(s) 2018. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle General Article
Pérez-Brangulí, Francesc
Buchsbaum, Isabel Y
Pozner, Tatyana
Regensburger, Martin
Fan, Wenqiang
Schray, Annika
Börstler, Tom
Mishra, Himanshu
Gräf, Daniela
Kohl, Zacharias
Winkler, Jürgen
Berninger, Benedikt
Cappello, Silvia
Winner, Beate
Human SPG11 cerebral organoids reveal cortical neurogenesis impairment
title Human SPG11 cerebral organoids reveal cortical neurogenesis impairment
title_full Human SPG11 cerebral organoids reveal cortical neurogenesis impairment
title_fullStr Human SPG11 cerebral organoids reveal cortical neurogenesis impairment
title_full_unstemmed Human SPG11 cerebral organoids reveal cortical neurogenesis impairment
title_short Human SPG11 cerebral organoids reveal cortical neurogenesis impairment
title_sort human spg11 cerebral organoids reveal cortical neurogenesis impairment
topic General Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400051/
https://www.ncbi.nlm.nih.gov/pubmed/30476097
http://dx.doi.org/10.1093/hmg/ddy397
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