Event Abstract

Disease modeling of Angelman syndrome using hiPSC-derived cerebellar organoids

  • 1 Institute for Biotechnology and Bioengineering, Portugal
  • 2 Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon, Portugal

Angelman syndrome (AS) is an incurable neurodevelopmental disorder characterized by ataxia, intellectual disability, speech impairment, seizures, autism behavior and happy demeanor. Based on murine AS mouse models, several neuronal types of the central nervous system are functionally affected, including Purkinje and granule cells within the cerebellum. However, the contribution of the cerebellum to the pathophysiology of AS remains enigmatic and has only been functionally explored in mouse models. AS is caused by a loss of the maternal UBE3A allele on 15q11- q13 chromosomal region. Previous work in our lab showed that neurons generated from AS-derived iPSCs maintain their imprinting status of parental UBE3A locus undergoing neuron-specific silencing upon maturation, validating the use of iPSC-derived neurons for in vitro modeling of AS. In this work, AS patients-derived induced pluripotent stem cell (iPSC) lines are used to generate 3D cerebellar organoids recapitulating the development of human cerebellum, with the aim of understanding the involvement of the cerebellum in the pathophysiology of the disease. We are using an optimized protocol developed in our group that allows to achieve functional in vitro maturation of all major cerebellar neuronal types such as Purkinje cells, Golgi cells, granule cells and non-Golgi-type interneurons. A comparison of cerebellar neurons obtained from three different AS-derived iPSC lines with those of two control (healthy) iPSC lines revealed that the generation of all GABAergic neuronal types is severely reduced in all AS conditions, with an excessive production of rhombic lip (glutamatergic) derivatives. AS-derived cerebellar aggregates have reduced size, showing a decrease in cerebellar ventricular markers KIRREL2, OLIG2 and CORL2 together with a decrease in PAX6 and PAX2 RNA levels. Ongoing experiments are focused on functional analysis of AS-derived neurons, as well as on the thorough evaluation of different neuronal types generated in these cultures, with quantitative assessment of proliferation and apoptosis during in vitro cerebellar differentiation of AS- derived and healthy iPSCs.


This work was supported by Fundação para a Ciência e a Tecnologia, Portugal (UID/BIO/04565/2013 and PD/BD/135505/2018 to C.M.; SFRH/BPD/81627/2011 to S.H.V.); LISBOA-01-0145-FEDER-007391/007317/029298, and PAC-PRECISE-LISBOA-01-0145- FEDER-016394, projects cofunded by FEDER through POR Lisboa 2020 - Programa Operacional Regional de Lisboa PORTUGAL 2020, and Fundação para a Ciência e a Tecnologia

Keywords: Angelman Syndrome, HiPSCs, Organoids, Cerebellum, Ataxia

Conference: XVI Meeting of the Portuguese Society for Neuroscience (SPN2019), Lisboa, Portugal, 30 May - 1 Jun, 2019.

Presentation Type: Pitch communication + Poster presentation

Topic: Rare Disorders

Citation: Maranga C, Da Silva TP, Vaz S, Da Rocha ST, Fernandes TG, Bekman EP and Cabral JS (2019). Disease modeling of Angelman syndrome using hiPSC-derived cerebellar organoids. Front. Cell. Neurosci. Conference Abstract: XVI Meeting of the Portuguese Society for Neuroscience (SPN2019). doi: 10.3389/conf.fncel.2019.01.00041

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Received: 16 Apr 2019; Published Online: 27 Sep 2019.

* Correspondence: Prof. Joaquim S Cabral, Institute for Biotechnology and Bioengineering, Lisbon, Portugal, joaquim.cabral@ist.utl.pt

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