Human SPG11 cerebral organoids reveal cortical neurogenesis impairment

Francesc Perez-Branguli; Isabel Y Buchsbaum; Tatyana Pozner; Martin Regensburger; Wenqiang Fan; Annika Schray; Tom Börstler; Himanshu Mishra; Daniela Gräf; Zacharias Kohl; Jürgen Winkler; Benedikt Berninger; Silvia Cappello; Beate Winner

doi:10.1093/hmg/ddy397

Human SPG11 cerebral organoids reveal cortical neurogenesis impairment

Francesc Perez-Branguli, Isabel Y Buchsbaum, Tatyana Pozner, Martin Regensburger, Wenqiang Fan, Annika Schray, Tom Börstler, Himanshu Mishra, Daniela Gräf, Zacharias Kohl, Jürgen Winkler, Benedikt Berninger, Silvia Cappello, Beate Winner

Developmental Neurobiology

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Abstract

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.

Original language	English
Journal	Human Molecular Genetics
Early online date	22 Nov 2018
DOIs	https://doi.org/10.1093/hmg/ddy397
Publication status	E-pub ahead of print - 22 Nov 2018

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title = "Human SPG11 cerebral organoids reveal cortical neurogenesis impairment",

abstract = "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{\textquoteright} 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.",

author = "Francesc Perez-Branguli and Buchsbaum, {Isabel Y} and Tatyana Pozner and Martin Regensburger and Wenqiang Fan and Annika Schray and Tom B{\"o}rstler and Himanshu Mishra and Daniela Gr{\"a}f and Zacharias Kohl and J{\"u}rgen Winkler and Benedikt Berninger and Silvia Cappello and Beate Winner",

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doi = "10.1093/hmg/ddy397",

language = "English",

journal = "Human Molecular Genetics",

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T1 - Human SPG11 cerebral organoids reveal cortical neurogenesis impairment

AU - Perez-Branguli, Francesc

AU - Buchsbaum, Isabel Y

AU - Pozner, Tatyana

AU - Regensburger, Martin

AU - Fan, Wenqiang

AU - Schray, Annika

AU - Börstler, Tom

AU - Mishra, Himanshu

AU - Gräf, Daniela

AU - Kohl, Zacharias

AU - Winkler, Jürgen

AU - Berninger, Benedikt

AU - Cappello, Silvia

AU - Winner, Beate

PY - 2018/11/22

Y1 - 2018/11/22

N2 - 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.

AB - 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.

U2 - 10.1093/hmg/ddy397

DO - 10.1093/hmg/ddy397

M3 - Article

SN - 0964-6906

JO - Human Molecular Genetics

JF - Human Molecular Genetics

ER -

Human SPG11 cerebral organoids reveal cortical neurogenesis impairment

Abstract

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