TY  - JOUR
AU  - Kagermeier, Theresa
AU  - Hauser, Stefan
AU  - Sarieva, Kseniia
AU  - Laugwitz, Lucia
AU  - Groeschel, Samuel
AU  - Janzarik, Wibke G
AU  - Yentür, Zeynep
AU  - Becker, Katharina
AU  - Schöls, Ludger
AU  - Kragelöh-Mann, Ingeborg
AU  - Mayer, Simone
TI  - Human organoid model of pontocerebellar hypoplasia 2a recapitulates brain region-specific size differences.
JO  - Disease models & mechanisms
VL  - 17
IS  - 7
SN  - 1754-8403
CY  - Cambridge
PB  - Company of Biologists Limited
M1  - DZNE-2024-00902
SP  - dmm050740
PY  - 2024
AB  - 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.
KW  - Humans
KW  - Organoids: pathology
KW  - Induced Pluripotent Stem Cells: metabolism
KW  - Induced Pluripotent Stem Cells: pathology
KW  - Male
KW  - Brain: pathology
KW  - Cell Differentiation
KW  - Cerebellum: abnormalities
KW  - Cerebellum: pathology
KW  - Olivopontocerebellar Atrophies: pathology
KW  - Olivopontocerebellar Atrophies: genetics
KW  - Cell Proliferation
KW  - Organ Size
KW  - Models, Biological
KW  - Apoptosis
KW  - Cerebellar Diseases
KW  - Apoptosis (Other)
KW  - Cerebellum (Other)
KW  - Differentiation (Other)
KW  - Organoid (Other)
KW  - PCH2a (Other)
KW  - Rare disease (Other)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC11552497
C6  - pmid:39034883
DO  - DOI:10.1242/dmm.050740
UR  - https://pub.dzne.de/record/270812
ER  -