The AKT2/SIRT5/TFEB pathway as a potential therapeutic target in atrophic AMD

Ghosh, S.; Sharma, R.; Bammidi, S.; Koontz, V.; Nemani, M.; Yazdankhah, M.; Kedziora, K. M.; Wallace, C. T.; Yu-Wei, C.; Franks, J.; Bose, D.; Rajasundaram, D.; Hose, S.; Sahel, J.-A.; Puertollano, R.; Finkel, T.; Zigler, J. S.; Sergeev, Y.; Watkins, S. C.; Goetzman, E. S.; Flores-Bellver, M.; Kaarniranta, K.; Sodhi, A.; Bharti, K.; Handa, J. T.; Sinha, D.

doi:10.1101/2023.08.08.552343

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bioRxiv · 10.1101/2023.08.08.552343

The AKT2/SIRT5/TFEB pathway as a potential therapeutic target in atrophic AMD

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Abstract

Introductory paragraphAge-related macular degeneration (AMD), the leading cause of geriatric blindness, is a multi-factorial disease with retinal-pigmented epithelial (RPE) cell dysfunction as a central pathogenic driver. With RPE degeneration, lysosomal function is a core process that is disrupted. Transcription factors EB/E3 (TFEB/E3) tightly control lysosomal function; their disruption can cause aging disorders, such as AMD. Here, we show that induced pluripotent stem cells (iPSC)-derived RPE cells with the complement factor H variant [CFH (Y402H)] have increased AKT2, which impairs TFEB/TFE3 nuclear translocation and lysosomal function. Increased AKT2 can inhibit PGC1, which downregulates SIRT5, an AKT2 binding partner. SIRT5 and AKT2 co-regulate each other, thereby modulating TFEB-dependent lysosomal function in the RPE. Failure of the AKT2/SIRT5/TFEB pathway in the RPE induced abnormalities in the autophagy-lysosome cellular axis by upregulating secretory autophagy, thereby releasing a plethora of factors that likely contribute to drusen formation, a hallmark of AMD. Finally, overexpressing AKT2 in RPE cells in mice led to an AMD-like phenotype. Thus, targeting the AKT2/SIRT5/TFEB pathway could be a potential therapy for atrophic AMD.

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Ghosh, S., Sharma, R., Bammidi, S., Koontz, V., Nemani, M., Yazdankhah, M., Kedziora, K. M., Wallace, C. T., Yu-Wei, C., Franks, J., Bose, D., Rajasundaram, D., Hose, S., Sahel, J.-A., Puertollano, R., Finkel, T., Zigler, J. S., Sergeev, Y., Watkins, S. C., Goetzman, E. S., Flores-Bellver, M., Kaarniranta, K., Sodhi, A., Bharti, K., Handa, J. T., Sinha, D.. 2023-08-09. The AKT2/SIRT5/TFEB pathway as a potential therapeutic target in atrophic AMD. https://doi.org/10.1101/2023.08.08.552343

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