Journal Article

DZNE-2024-00902

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Human organoid model of pontocerebellar hypoplasia 2a recapitulates brain region-specific size differences.

Kagermeier, T. ; Hauser, S.DZNE* ; Sarieva, K. ; Laugwitz, L. ; Groeschel, S. ; Janzarik, W. G. ; Yentür, Z. ; Becker, K. ; Schöls, L.DZNE* ; Kragelöh-Mann, I. ; Mayer, S.

2024
Company of Biologists Limited Cambridge

This record in other databases:  

Please use a persistent id in citations: doi:10.1242/dmm.050740

Abstract: 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.

Keyword(s): Humans (MeSH) ; Organoids: pathology (MeSH) ; Induced Pluripotent Stem Cells: metabolism (MeSH) ; Induced Pluripotent Stem Cells: pathology (MeSH) ; Male (MeSH) ; Brain: pathology (MeSH) ; Cell Differentiation (MeSH) ; Cerebellum: abnormalities (MeSH) ; Cerebellum: pathology (MeSH) ; Olivopontocerebellar Atrophies: pathology (MeSH) ; Olivopontocerebellar Atrophies: genetics (MeSH) ; Cell Proliferation (MeSH) ; Organ Size (MeSH) ; Models, Biological (MeSH) ; Apoptosis (MeSH) ; Cerebellar Diseases (MeSH) ; Apoptosis ; Cerebellum ; Differentiation ; Organoid ; PCH2a ; Rare disease

---

Contributing Institute(s):

1. Clinical Neurogenetics (AG Schöls)
2. Advanced cellular models of neurodegeneration (AG Hauser)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)
2. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2024

---

Database coverage:
; ; ; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF < 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

---