Luminopsin-mediated stimulation of transplanted dopaminergic cells in unilateral 6-OHDA lesion model of Parkinson's disease

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Abstract

LUMINOPSIN-MEDIATED STIMULATION OF TRANSPLANTED DOPAMINERGICCELLS IN UNILATERAL 6-OHDA LESION MODEL OF PARKINSON’S DISEASEKevin A. Anderson, Eric D. Peterson, Akash Pal, Erica L. Burkett, Rachel A. Byrd, Bailey J.Whitehead, Andrew S. Hauler, Romualdo R. Ancog, Kaitlynn E. Azinger, Monica D. Hill, UteHochgeschwender, & Michael I. SandstromOf the treatments for Parkinson’s disease (PD), a neurodegenerative disorder resulting from the degradation of dopaminergic (DA) neurons in the substantia nigra, stem cell transplantation demonstrates high potential. Preclinical data suggests a waning of benefit prior to or without significant disruption of the transplant. We theorize that a gradual adaptive response is occurring due to imprecise regulation of grafted cells. Under this hypothesis, controlling DA release would be imperative and stem cell therapy should strive to establish context-specific DA activity. Of the various tools for controlling cellular activity, one recent development shows promise: bioluminescent optogenetics. Bioluminescent optogenetics is an expansion of optogenetic technique that makes use of luminopsins—pairs of proteins comprised of a luciferase and an opsin. This provides the ability to activate the opsin by stimulating the luciferase with its associated substrate rather than with direct light. This study involved the creation of a stable transgenic mesenchymal stem cell line that expresses the luminopsin construct LMO3 and used these cells in a dopaminergic differentiation protocol followed by their in vivo transplantation into unilateral 6-OHDA lesioned rats. This model typically exhibits asymmetrical movements in the absence of treatment, and limb-use symmetry would indicate restoration of function. By using a repeated measures design where rats were injected with either the active substrate or an inert vehicle in randomized sequence, we compared benefits of transplants alone with those produced by stimulating luminopsin-expressing DA cells in restoring symmetrical limb use while the animals were swimming. This was done along with concurrent microdialysis to correlate dopamine release from the lesioned hemisphere with the animals’ symmetrical limb use.
Original languageEnglish
StatePublished - May 2018
Event49th Annual Meeting of the Michigan Chapter Society for Neuroscience - Wayne State University
Duration: May 1 2018May 31 2018

Conference

Conference49th Annual Meeting of the Michigan Chapter Society for Neuroscience
Period05/1/1805/31/18

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