Amino Acid and Lipid Metabolism Link Peripheral Neuropathy and Retinal Degeneration

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Friday, April 24, 2020 -
2:00pm to 3:00pm
Marin Gantner


Staff Scientist

Lowy Medical Research Institute (LMRI) in La Jolla California

Amino Acid and Lipid Metabolism Link Peripheral Neuropathy and Retinal Degeneration


The amino acid serine is central to mammalian cell metabolism. In addition to dietary sources of serine, homeostatic levels are maintained by de novo synthesis via the enzyme phosphoglycerate dehydrogenase (PHGDH). Altered serine metabolism has been linked to the retinal degenerative disease MacTel. MacTel patients have reduced serum serine and glycine levels. Furthermore, genetic analyses have identified a risk locus, as well as rare variants, in PHGDH. If and how reduced serine levels and/or PHGDH activity lead to retinal disease is poorly understood. Based on rare cases of MacTel with a co-morbidity for a peripheral neuropathy, HSAN1, we identified a convergence of the two diseases on the accumulation of downstream toxic lipids, deoxysphingolipids (deoxySL). In patients with HSAN1, elevated deoxySL levels are a consequence of mutations in the enzyme serine palmitoyltransferase (SPT), which leads to both the peripheral neuropathy and MacTel. Interestingly, we find that in the broader MacTel population, without HSAN1, increased deoxySL levels are driven by low serine levels. Working with human retinal organoids we find deoxySL are toxic to retinal cells and likely part of the disease etiology. Using various dietary and genetic mouse models we show that the retina relies on multiple serine sources and is highly sensitive to disruption of serine metabolism, resulting in increased deoxySLs and retinal dysfunction.



Dr. Marin Gantner is a Staff Scientist at the Lowy Medical Research Institute (LMRI) in La Jolla California, an institute focused on studying the retinal degenerative disease, macular telangiectasia type 2 (MacTel). She received her Ph.D. from The Scripps Research Institute, working on understanding the signaling pathways and transcription responses that regulate energy metabolism.  Dr. Gantner is applying her metabolic background and perspective to understanding the unique metabolic landscape of the retina. She currently heads LMRI’s metabolism research program, with a focus on metabolism in the retina. She works with an international network of clinical sites to coordinate the collection of patient samples to help drive disease-based discovery. Her research combines the use of these clinical samples, cellular and animal models to gain insight into the normal metabolic demands of the retina and understanding how these change with disease. Her current focus is investigating serine, glycine and sphingolipid metabolism in the retina as it relates to changes observed in MacTel patients. These findings are being translated back into the clinic, guiding pilot studies to improve the treatment of MacTel.