Research Paper Volume 13, Issue 8 pp 10866—10890
Pharmacologic activation of autophagy without direct mTOR inhibition as a therapeutic strategy for treating dry macular degeneration
- 1 Kellogg Eye Center, University of Michigan, Ann Arbor, MI 48105, USA
- 2 KCL Centre for Cell and Gene Therapy, London, England WC2R 2LS, United Kingdom
- 3 Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48105, USA
Received: September 8, 2020 Accepted: March 13, 2021 Published: April 19, 2021https://doi.org/10.18632/aging.202974
How to Cite
Copyright: © 2021 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Dry age-related macular degeneration (AMD) is marked by the accumulation of extracellular and intracellular lipid-rich deposits within and around the retinal pigment epithelium (RPE). Inducing autophagy, a conserved, intracellular degradative pathway, is a potential treatment strategy to prevent disease by clearing these deposits. However, mTOR inhibition, the major mechanism for inducing autophagy, disrupts core RPE functions. Here, we screened autophagy inducers that do not directly inhibit mTOR for their potential as an AMD therapeutic in primary human RPE culture. Only two out of more than thirty autophagy inducers tested reliably increased autophagy flux in RPE, emphasizing that autophagy induction mechanistically differs across distinct tissues. In contrast to mTOR inhibitors, these compounds preserved RPE health, and one inducer, the FDA-approved compound flubendazole (FLBZ), reduced the secretion of apolipoprotein that contributes to extracellular deposits termed drusen. Simultaneously, FLBZ increased production of the lipid-degradation product β-hydroxybutyrate, which is used by photoreceptor cells as an energy source. FLBZ also reduced the accumulation of intracellular deposits, termed lipofuscin, and alleviated lipofuscin-induced cellular senescence and tight-junction disruption. FLBZ triggered compaction of lipofuscin-like granules into a potentially less toxic form. Thus, induction of RPE autophagy without direct mTOR inhibition is a promising therapeutic approach for dry AMD.
AMD: age-related macular degeneration; ApoE: apolipoprotein E; β-HB: beta-hydroxybutyrate; FDA: (US) Federal Drug Administration; FLBZ: flubendazole; GSK: GSK 1059615 (dual mTOR and phosphoinositide-3-kinase inhibitor); hfRPE: human fetal retinal pigment epithelium (cultures); JNJ: JNJ-47965567 (P2X7 purinergic receptor antagonist); KB: ketone body; LC3: microtubule-associated protein 1A/1B-light chain 3; LDH: lactate dehydrogenase; mTOR: mammalian target of rapamycin; MT: microtubule; OS: (photoreceptor) outer segments; oxOS: photo-oxidized (photoreceptor) outer segments; RPE: retinal pigment epithelium; TEER: trans-epithelial electrical resistance; Torin: torin1 (mTOR inhibitor); UAM: undigestible autofluorescent material (lipofuscin-like material).