Retina Society 2018: The Charles L. Schepens Lecture - Regenerative visual neuroscience: how it will transform eye care by Dr. Paul Sternberg


Thomas J. Wubben, MD, PhD Vitreoretinal Surgery Fellow Kellogg Eye Center / University of Michigan Congratulations to Dr. Wubben from Kellogg Eye Center, who is the 2018 recipient of the Retina Society Fellowship Research Award. He's on quite the run, also being awarded the Michels Fellowship Award just 2 weeks ago. We are honored to have Dr. Wubben discuss his groundbreaking work on neuroprotection with us, which he presented this past week at the Retina Society meeting in San Francisco. [caption id="attachment_2428" align="alignnone" width="1788"]image7 Dr. Thomas Wubben[/caption]

Can you tell our readers about your study?

Wubben: As many of the readers know, photoreceptor cell death is the root cause of vision loss in many retinal disorders. No successful treatment options currently exist to prevent photoreceptor cell loss. Therefore, there is an urgent unmet need for neuroprotective modalities to improve photoreceptor survival. Considering photoreceptors have little reserve capacity to generate ATP (energy for the cell) and as a result, are susceptible to small changes in energy homeostasis, disruption of nutrient availability and metabolic regulation may be a unifying mechanism in photoreceptor cell death. The biosynthetic requirement of photoreceptors is among the highest in the body, and to meet this demand, photoreceptors maintain their ability to perform aerobic glycolysis. This highly regulated form of glucose metabolism allows cells to efficiently budget their metabolic needs and may be a critical link between photoreceptor function and survival. Pyruvate kinase muscle isozyme 2 (PKM2) is a key regulator of aerobic glycolysis. As such, the over-arching hypothesis of our study is that metabolic reprogramming of photoreceptor glucose metabolism will increase the efficiency of energy generation and enhance photoreceptor survival during periods of outer retinal stress. The goal specific to this project was to genetically reprogram photoreceptor glucose metabolism by altering the expression of PKM2.

What did you find?

To begin to understand our results, one needs to know that PKM2 is unique to aerobic glycolysis, is under complex regulation to provide a high and low activity state depending on nutrient availability as well as other regulators, and localizes to photoreceptors. Its isoform, PKM1, is predominantly found in the inner retina and has only constitutively high catalytic activity. With that understanding, we generated a knockout mouse model with selective deletion of PKM2 in photoreceptors, which led to compensatory PKM1 expression and upregulation of genes involved in glucose metabolism. Under acute stress produced by experimental retinal detachment, this mouse model showed decreased photoreceptor apoptosis and increased photoreceptor survival. We also showed that the regulation of PKM2 in rodent retina shifts to the high activity state after experimental retinal detachment to increase catabolic activity. Thus, the metabolic reprogramming observed in the retina of the photoreceptor-specific Pkm2 knockout mice mimics the activation of PKM2 after nutrient deprivation by substituting constitutively active PKM1 to circumvent acute apoptotic stress and increase photoreceptor survival.

How can this study be translated into a novel therapeutic strategy to improve photoreceptor survival and ultimately vision in many individuals?

Our results provide evidence that reprogramming of photoreceptor metabolism is a novel therapeutic strategy for photoreceptor neuroprotection. The knockout mouse model we generated with selective deletion of PKM2 in photoreceptors and compensatory PKM1 isoform expression showed increased PK activity. Hence, a small-molecule activator that activates PKM2 and increases its catalytic activity may show similar photoreceptor neuroprotective effects and be translated to the clinic to improve vision in many suffering from retinal disorders. However, further research is needed.