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See detailGeneration of midbrain organoids as a model to study Parkinson's disease
Smits, Lisa UL

Doctoral thesis (2019)

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 ... [more ▼]

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. [less ▲]

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See detailSingle-cell transcriptomics reveals multiple neuronal cell types in human midbrain-specific organoids
Smits, Lisa UL; Magni, Stefano UL; Grzyb, Kamil UL et al

E-print/Working paper (2019)

Human stem cell-derived organoids have great potential for modelling physiological and pathological processes. They recapitulate in vitro the organisation and function of a respective organ or part of an ... [more ▼]

Human stem cell-derived organoids have great potential for modelling physiological and pathological processes. They recapitulate in vitro the organisation and function of a respective organ or part of an organ. Human midbrain organoids (hMOs) have been described to contain midbrain-specific dopaminergic neurons that release the neurotransmitter dopamine. However, the human midbrain contains also additional neuronal cell types, which are functionally interacting with each other. Here, we analysed hMOs at high-resolution by means of single-cell RNA-sequencing (scRNA-seq), imaging and electrophysiology to unravel cell heterogeneity. Our findings demonstrate that hMOs show essential neuronal functional properties as spontaneous electrophysiological activity of different neuronal subtypes, including dopaminergic, GABAergic, and glutamatergic neurons. Recapitulating these in vivo features makes hMOs an excellent tool for in vitro disease phenotyping and drug discovery. [less ▲]

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See detailModeling Parkinson’s disease in midbrain-like organoids
Smits, Lisa UL; Reinhardt, Lydia; Reinhardt, Peter et al

in NPJ Parkinson's Disease (2019)

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See detailActivity of translation regulator eukaryotic elongation factor-2 kinase is increased in Parkinson disease brain and its inhibition reduces alpha synuclein toxicity
Jan, Asad; Jansonius, Brandon; Delaidelli, Alberto et al

in Acta Neuropathologica Communications (2018)

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See detailNurr1:RXRα heterodimer activation as monotherapy for Parkinson’s disease
Spathis, Athanasios; Asvos, Xenophon; Ziavra, Despina et al

in Proceedings of the National Academy of Sciences of the United States of America (2017)

Detailed reference viewed: 108 (4 UL)