Reference : Generation of midbrain organoids as a model to study Parkinson's disease
Dissertations and theses : Doctoral thesis
Life sciences : Biochemistry, biophysics & molecular biology
Generation of midbrain organoids as a model to study Parkinson's disease
Smits, Lisa mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
University of Luxembourg, ​​Luxembourg
Docteur en Biologie
Schwamborn, Jens Christian mailto
Grünewald, Anne mailto
Skupin, Alexander mailto
Mandemakers, Wim
[en] Parkinson's disease ; midbrain organoids ; stem cells
[en] The study of 3D cell culture models not only bridges the gap between traditional 2D in vitro experiments and in vivo animal models, it also addresses processes that cannot be recapitulated by these traditional models. Therefore, it offers an opportunity to better understand complex biology, for instance brain development, where conventional models have not proven successful. The so{called brain organoid technology provides a physiologically relevant context, which holds great potential for its application in modelling neurological diseases. To obtain these highly specialised structures, resembling specifically key features of
the human midbrain, we derived a human midbrain-specific organoid (hMO) system from regionally patterned neural stem cells (NSCs). The resulting neural tissue exhibited abundant neurons with midbrain dopaminergic neuron (mDAN) identity, as well as astroglia and oligodendrocyte di erentiation. Within the hMOs, we could observe neurite myelination and the formation of synaptic connections. Regular fire patterning and neural network synchronicity were determined by multielectrode array (MEA) recordings. In addition to electrophysiologically functional mDANs producing and secreting dopamine (DA), we also detected responsive neuronal subtypes, like GABAergic and glutamatergic neurons.
To investigate Parkinson's disease (PD)-relevant pathomechanisms, we derived hMOs from PD patients carrying the LRRK2-G2019S mutation and compared them to healthy control hMOs. In addition to a reduced number and complexity of mDANs, we determined a signi cant increase of the stem cell marker FOXA2 in the patient-derived hMOs. This suggests a neurodevelopmental defect induced by a PD-specific mutation and emphasises the importance of advanced three-dimensional (3D) stem cell-based in vitro models.
The in this thesis described hMOs are suitable to reveal PD{relevant phenotypes, thus constitute as a powerful tool for human-specific in vitro disease modelling of neurological disorders with a great potential to be utilised in advanced therapy development.
Luxembourg Centre for Systems Biomedicine (LCSB)
Fonds National de la Recherche - FnR
Researchers ; Professionals ; Students ; General public
FnR ; FNR9137778 > Lisa Maria Smits > > Cellular Mosaicism as a cause for Parkinson’s disease. > 01/07/2015 > 30/06/2019 > 2014

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