Doctoral thesis (Dissertations and theses)
Modeling Parkinson's disease using human midbrain organoids
Monzel, Anna Sophia
2019
 

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Keywords :
Organoids; Stem cells; Parkinson's disease
Abstract :
[en] With increasing prevalence, neurodegenerative disorders present a major challenge for medical research and public health. Despite years of investigation, significant knowledge gaps exist, which impede the development of disease-modifying therapies. The development of tools to model both physiological and pathological human brains greatly enhanced our ability to study neurological disorders. Brain organoids, derived from human induced pluripotent stem cells (iPSCs), hold unprecedented promise for biomedical research to unravel novel pathological mechanisms of a multitude of brain disorders. As brain proxies, these models bridge the gap between traditional 2D cell cultures and animal models. Owing to their human origin, hiPSC-derived organoids can recapitulate features that cannot be modeled in animals by virtue of differences in species. Parkinson’s disease (PD) is a human-specific neurodegenerative disorder. The major manifestations are the consequence of degenerating dopaminergic neurons (DANs) in the midbrain. The disease has a multifactorial etiology and a multisystemic pathogenesis and pathophysiology. In this thesis, we used state-of-the-art technologies to develop a human midbrain organoid (hMO) model with a great potential to study PD. hMOs were generated from iPSC-derived neural precursor cells, which were pre-patterned to the midbrain/hindbrain region. hMOs contain multiple midbrain-specific cell types, such as midbrain DANs, as well as astrocytes and oligodendrocytes. We could demonstrate features of neuronal maturation such as myelination, synaptic connections, spontaneous electrophysiological activity and neural network synchronicity. We further developed a neurotoxin-induced PD organoid model and set up a high-content imaging platform coupled with machine learning classification to predict neurotoxicty. Patient-derived hMOs display PD-relevant pathomechanisms, indicative of neurodevelopmental deficits. hMOs as novel in vitro models open up new avenues to unravel PD pathophysiology and are powerful tools in biomedical research.
Research center :
Luxembourg Centre for Systems Biomedicine (LCSB)
Disciplines :
Life sciences: Multidisciplinary, general & others
Neurology
Author, co-author :
Monzel, Anna Sophia ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Language :
English
Title :
Modeling Parkinson's disease using human midbrain organoids
Defense date :
25 November 2019
Number of pages :
229
Institution :
Unilu - University of Luxembourg, Luxembourg
Degree :
Docteur en Biologie
President :
Jury member :
Fitzgerald, Julia
Wade-Martins, Richard
Focus Area :
Systems Biomedicine
FnR Project :
FNR9990181 - Development And Validation Of A Human Three-dimensional In Vitro Midbrain Model, 2015 (15/11/2015-14/11/2019) - Anna Sophia Monzel
Funders :
FNR - Fonds National de la Recherche [LU]
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since 06 December 2019

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