Home > Publications Database > Human organoid model of pontocerebellar hypoplasia 2a recapitulates brain region-specific size differences. > print

001     270812
005     20250127091658.0
024 7 _ |a pmc:PMC11552497
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024 7 _ |a 10.1242/dmm.050740
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037 _ _ |a DZNE-2024-00902
041 _ _ |a English
082 _ _ |a 570
100 1 _ |a Kagermeier, Theresa
|0 0000-0002-7557-8523
|b 0
245 _ _ |a Human organoid model of pontocerebellar hypoplasia 2a recapitulates brain region-specific size differences.
260 _ _ |a Cambridge
|c 2024
|b Company of Biologists Limited
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520 _ _ |a 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.
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650 _ 7 |a Apoptosis
|2 Other
650 _ 7 |a Cerebellum
|2 Other
650 _ 7 |a Differentiation
|2 Other
650 _ 7 |a Organoid
|2 Other
650 _ 7 |a PCH2a
|2 Other
650 _ 7 |a Rare disease
|2 Other
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Organoids: pathology
|2 MeSH
650 _ 2 |a Induced Pluripotent Stem Cells: metabolism
|2 MeSH
650 _ 2 |a Induced Pluripotent Stem Cells: pathology
|2 MeSH
650 _ 2 |a Male
|2 MeSH
650 _ 2 |a Brain: pathology
|2 MeSH
650 _ 2 |a Cell Differentiation
|2 MeSH
650 _ 2 |a Cerebellum: abnormalities
|2 MeSH
650 _ 2 |a Cerebellum: pathology
|2 MeSH
650 _ 2 |a Olivopontocerebellar Atrophies: pathology
|2 MeSH
650 _ 2 |a Olivopontocerebellar Atrophies: genetics
|2 MeSH
650 _ 2 |a Cell Proliferation
|2 MeSH
650 _ 2 |a Organ Size
|2 MeSH
650 _ 2 |a Models, Biological
|2 MeSH
650 _ 2 |a Apoptosis
|2 MeSH
650 _ 2 |a Cerebellar Diseases
|2 MeSH
700 1 _ |a Hauser, Stefan
|0 P:(DE-2719)2810998
|b 1
700 1 _ |a Sarieva, Kseniia
|0 0000-0002-0579-6090
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700 1 _ |a Laugwitz, Lucia
|0 0000-0003-2506-1961
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700 1 _ |a Groeschel, Samuel
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700 1 _ |a Janzarik, Wibke G
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700 1 _ |a Yentür, Zeynep
|0 0000-0002-4832-9927
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700 1 _ |a Becker, Katharina
|0 0000-0002-6479-3762
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700 1 _ |a Schöls, Ludger
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700 1 _ |a Kragelöh-Mann, Ingeborg
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700 1 _ |a Mayer, Simone
|0 0000-0002-6381-2474
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773 _ _ |a 10.1242/dmm.050740
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910 1 _ |a Deutsches Zentrum für Neurodegenerative Erkrankungen
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