Dissecting the functionality of dopaminergic grafts for parkinsons disease with optogenetics

• Applicant: Dr. Julius A. Steinbeck
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2012 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 206551838

One of the major avenues of hope for neurodegenerative diseases, e.g. Parkinson’s disease, lies in the field of regenerative medicine.In this regard, the knowledge to generate therapeutically relevant neural donor cells in unlimited numbers from pluripotent stem cells has opened new prospects for nervous system repair. While human neural donor cells were shown to survive, differentiate, grow axons, establish ultrastructural correlates of synaptic connections and receive synaptic input after transplantation, the question of functional graft to host-connectivity is still completely unresolved, mainly because efficient tools to address this question were not available. However, the question of graft to host-connectivity is essential since therapeutic effects might also be achievable through trophic support or other unspecific mechanisms after neural stem cell transplantation rather than real network integration.I plan to address the question of graft to host-connectivity by making use of a recently introduced technique called optogenetics. This technique is based on microbial light sensitive ion channels (channelrhodopsins), which can be expressed under cell type specific promoters and used to hyper- or depolarize neuronal cells in response to light. I will generate human ES cell lines expressing depolarizing (activating) and hyperpolarizing (deactivating) channelrhodopsins under the control of the neuron-specific synapsin promotor. Upon dopaminergic differentiation of these cells, brief application of light pulses should suffice in functional activation or inhibition, resulting in increased or decreased dopamine release. After transplantation of these cells into the denervated striatum (animal model of Parkinson’s disease) the therapeutic effect attributable to network integration should be assessable through intrastriatal application of light pulses during behavioral testing.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Lorenz Studer