Human organoid model of pontocerebellar hypoplasia 2a recapitulates brain region-specific size differences.

Autor:	Kagermeier T; Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.; Graduate Training Centre of Neuroscience, University of Tübingen, 72076 Tübingen, Germany., Hauser S; Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.; German Center for Neurodegenerative Diseases, 72076 Tübingen, Germany., Sarieva K; Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.; Graduate Training Centre of Neuroscience, University of Tübingen, 72076 Tübingen, Germany.; International Max Planck Research School, Graduate Training Centre of Neuroscience, University of Tübingen, 72076 Tübingen, Germany., Laugwitz L; Department of Neuropediatrics, Developmental Neurology and Social Pediatrics, University of Tübingen, 72076 Tübingen, Germany., Groeschel S; Department of Neuropediatrics, Developmental Neurology and Social Pediatrics, University of Tübingen, 72076 Tübingen, Germany., Janzarik WG; Department of Neuropediatrics and Muscle Disorders, Center for Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany., Yentür Z; Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.; Graduate Training Centre of Neuroscience, University of Tübingen, 72076 Tübingen, Germany.; International Max Planck Research School, Graduate Training Centre of Neuroscience, University of Tübingen, 72076 Tübingen, Germany.; Heidelberger Akademie der Wissenschaften, 69117 Heidelberg, Germany., Becker K; Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany., Schöls L; Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.; German Center for Neurodegenerative Diseases, 72076 Tübingen, Germany., Krägeloh-Mann I; Department of Neuropediatrics, Developmental Neurology and Social Pediatrics, University of Tübingen, 72076 Tübingen, Germany., Mayer S; Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.; Heidelberger Akademie der Wissenschaften, 69117 Heidelberg, Germany.
Jazyk:	angličtina
Zdroj:	Disease models & mechanisms [Dis Model Mech] 2024 Jul 01; Vol. 17 (7). Date of Electronic Publication: 2024 Jul 22.
DOI:	10.1242/dmm.050740
Abstrakt:	Pontocerebellar hypoplasia type 2a (PCH2a) is an ultra-rare, autosomal recessive pediatric disorder with limited treatment options. Its anatomical hallmark is hypoplasia of the cerebellum and pons accompanied by progressive microcephaly. A homozygous founder variant in TSEN54, which encodes a tRNA splicing endonuclease (TSEN) complex subunit, is causal. The pathological mechanism of PCH2a remains unknown due to the lack of a model system. Therefore, we developed human models of PCH2a using regionalized neural organoids. We generated induced pluripotent stem cell (iPSC) lines from three males with genetically confirmed PCH2a and subsequently differentiated cerebellar and neocortical organoids. Mirroring clinical neuroimaging findings, PCH2a cerebellar organoids were reduced in size compared to controls starting early in differentiation. Neocortical PCH2a organoids demonstrated milder growth deficits. Although PCH2a cerebellar organoids did not upregulate apoptosis, their stem cell zones showed altered proliferation kinetics, with increased proliferation at day 30 and reduced proliferation at day 50 compared to controls. In summary, we generated a human model of PCH2a, providing the foundation for deciphering brain region-specific disease mechanisms. Our first analyses suggest a neurodevelopmental aspect of PCH2a. Competing Interests: Competing interests The authors declare no competing or financial interests. (© 2024. Published by The Company of Biologists Ltd.)
Databáze:	MEDLINE
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