8th International Wolfram Symposium Presentation Dr. Vania Broccoli – CNR – National Research Council Institute of Neuroscience, Milan. Italy

8th International Wolfram Symposium Presentation Dr. Vania Broccoli – CNR – National Research Council Institute of Neuroscience, Milan. Italy.

New function of Wolframin in regulating the monocarboxylate transporter 1 (MCT1) in glial cells in brain and retina.

Abstract: A key pathological manifestation in Wolfram syndrome is the progressive optic atrophy which leads to relentless visual loss. Although some of the pathological mechanisms caused by wolframin mutations have been unraveled in the recent years, how they impinge on visual deficits it remains unclear. Through genomics and proteomics analyses on retinal tissues isolated from wolframin mutant mice, we identified a significant reduction of the monocarboxylate transport isoform 1 (MCT1) and its partner basigin that are highly enriched on retinal glia and myelin- forming oligodendrocytes in optic nerve together with wolframin. Loss of MCT1 causes a failure in lactate transfer from glial to neuronal cell bodies and axons leading to a chronic hypometabolic state that can cause retinal ganglion cell (RGC) degeneration. This metabolic dysfunction occurs months before the frank RGC degeneration suggesting an extended time-window for intervening with new therapeutic strategies focused on boosting retinal and optic nerve bioenergetics in WS1.

Points noted:

• Retinal ganglion cells (RGCs) are vulnerable in WS, the genetic link to symptoms still needs to be understood.
• Mice WS KO model(s) were shared from Estonia (Dr Mario Plaas) – nerve damage and visual acuity loss are detected early (6-8 months) before very significant RGC loss (12 months).
• Developed working hypothesis of biochemical pathway alterations that lead to lack of energy metabolites and neuron loss.
• One future goal is to understand the structure of wolframin protein, (which is not easy!). Therefore, intend to collaborate with expert group based in New York.
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