Advanced modeling of Parkinson's disease with three-dimensional human midbrain organoids
Projectomschrijving
Prof. Vincenzo Bonifati van de afdeling klinische genetica van Erasmus MC, Rotterdam, heeft in een Europees samenwerkingsverband een nieuw modelsysteem voor de ziekte van Parkinson ontwikkeld. Door middel van innovatieve technieken zijn stamcellen (iPS cellen) geïnduceerd uit huidcellen van Parkinson patiënten, die vervolgens gedifferentieerd zijn naar het type zenuwcellen die afsterven in Parkinson patiënten. Door middel van deze techniek heeft Prof. Bonifati aangetoond dat in een bepaalde groep Parkinson patiënten met mutaties in het SYNJ1 gen er in het cellulaire afvalverwerking systeem, autofagie genoemd, een defect optreed. Tevens heeft het
Bonifati lab mutaties in het LRP10 gen ontdekt als een nieuwe oorzaak van erfelijke vormen van de ziekte van Parkinson. We hopen dat in de toekomst dit modelsysteem zal bijdragen aan meer kennis over oorzaken van de ziekte van Parkinson en anderzijds het ontwikkelen van therapieën die deze slopende ziekte kunnen vertragen of stoppen.
Verslagen
Samenvatting van de aanvraag
One of the main limitations in neuroscience and in the modeling of neurodegenerative diseases is the lack of advanced experimental in vitro models that truly recapitulate the complexity of the human brain. Therefore, it is the aim of the here proposed research project to generate brain-like organoids that resemble the human midbrain and their integration into a multifunctional lab-on-a-chip device. We will focus on Parkinson’s disease, which is the second most common neurodegenerative disease. The midbrains-on-a-chip will be generated from induced pluripotent stem cells derived from Parkinson’s disease patients that carry defined disease causing mutations as well as from idiopathic patients. This will allow us to elucidate how Parkinson’s disease imparts architectural remodeling, dopamine release and network formation of the midbrain tissue. The successful cultivation of in vitro midbrain organoids in a micro-analytical analysis platform will yield substantial insights and open new avenues for exploring the mechanisms of onset and progression under physiologically relevant measurement conditions. Moreover by the usage of microfluidics devices the whole approach is cost-effective and suitable for screening purposes. We hypothesize that Parkinson’s disease specific phenotypes that can be observed in these midbrain organoids are more relevant for the actual situation in patients than those that are observed in homogenous two-dimensional cultures of single cell types. Furthermore, we are convinced that continued and non-invasive monitoring of Parkinson’s disease specific phenotypes will lead to a more detailed understanding of dynamic disease processes. The three objectives of the proposed research include a) the generation of three-dimensional organoids using induced pluripotent stem cells derived from Parkinson’s disease patients; b) to develop a computer-controlled fully automated miniaturized 3D midbrain-on-a-chip system containing embedded optical and electrical microsensors to investigate dynamic cell-to-cell and cell-to-matrix interactions; and c) the examination of patient specific 3D midbrains to determine disease specific phenotypes. These advanced and personalized disease models will be the basis for a more detailed understanding of disease processes, as well as for future screenings to modulate or treat the disease.