Biological Light for Optogenetic Applications in Biomedicine

Biological light, or bioluminescence, is generated when a luciferase enzyme oxidizes a luciferin, a small molecule substrate. The emitted light enables activation of nearby photoreceptors, thus allowing to drive optogenetic elements from an internal cold light source when the substrate is administered. Advantages are the avoidance of implanted light fibers, the absence of heat damage, and the ability to reach every cell that expresses the luciferase-opsin combination rather than only those in the vicinity of a physical light source. We took advantage of this bioluminescent optogenetics approach in two preclinical applications that pose specific challenges to conventional optogenetics. In a spinal cord injury model in rats we genetically expressed a luminopsin (LMO3), a fusion protein of the light emitting Gaussia luciferase tethered to the light sensing Volvox channelrhodopsin 1, in motorneurons and interneurons below the site of injury (1). Neurons were activated by the addition of the luciferase substrate coelenterazine (CTZ), thus allowing non-invasive stimulation and recruitment of all targeted neurons. Neural stimulation starting a day after contusion injury of the thoracic spine for two weeks of either interneuron or motorneuron populations below the level of injury significantly improved locomotor recovery lasting beyond the time of stimulation. In a mouse Parkinsons model we utilized bioluminescent optogenetics to activate transplanted neural precursor cells (2). Remote stimulation of all transplanted cells expressing LMO3 by daily application of CTZ improved motor behavior in Parkinsons disease mice. This bioluminescent optogenetics approach might be beneficial across a wide range of stem cell transplantation therapies for optimal neural repair and functional recovery.

1. Petersen et al., Restoring function after severe spinal cord injury through bioluminescence-driven optogenetics. bioRxiv 710194, 2019
2. Zenchak et al., Bioluminescence-driven optogenetic activation of transplanted neural precursor cells improves motor deficits in a Parkinson's disease mouse model. J Neurosci Res. Mar 25, 2018