Reference : Modeling Parkinson's disease using human midbrain organoids
Dissertations and theses : Doctoral thesis
Life sciences : Multidisciplinary, general & others
Human health sciences : Neurology
Systems Biomedicine
http://hdl.handle.net/10993/41201
Modeling Parkinson's disease using human midbrain organoids
English
Monzel, Anna Sophia mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
25-Nov-2019
University of Luxembourg, ​​Luxembourg
Docteur en Biologie
229
Schwamborn, Jens Christian mailto
Krüger, Rejko mailto
Fitzgerald, Julia mailto
Wade-Martins, Richard mailto
[en] Organoids ; Stem cells ; Parkinson's disease
[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.
Luxembourg Centre for Systems Biomedicine (LCSB)
Fonds National de la Recherche - FnR
Researchers ; Professionals ; Students
http://hdl.handle.net/10993/41201
FnR ; FNR9990181 > Anna Sophia Monzel > > Development and validation of a human three-dimensional in vitro midbrain model > 15/11/2015 > 14/11/2019 > 2015

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