Abstract
Purpose :
Defective proteostasis is one of the hallmarks of aging cells and tissues. Of the different components of the proteostasis network, we are interested in autophagy and its changes with age in retina. We have previously shown that, out of the different autophagic pathways that co-exist in all mammalian cells, macroautophagy is the first that declines with age in the retina. A crosstalk between macroautophagy and chaperone mediated autophagy (CMA) has been described whereby, in aged mice retinas, the decrease in macroautophagy correlates with increased CMA. A similar upregulation of CMA can also be observed in the retina of a genetic mouse model deficient for macroautophagy and in rd10, a mouse model of retinitis pigmentosa. Our working hypothesis is that aged and degenerated retinal cells increase CMA to compensate for macroautophagy loss, in an attempt to maintain cell viability. If proven correct, increasing CMA could be a potential treatment to delay consequences of aging in the retina and to ameliorate degeneration in age-related retinal pathologies.
Methods :
We have used genetic approaches to modulate CMA in vivo, the LAMP-2A knockout mice and animals that overexpress the LAMP-2A protein after tamoxifen injection. We have assessed retinal morphology and visual function by electroretinogram.
Results :
Using a mouse model deficient for LAMP-2A, the lysosomal membrane protein essential for CMA, we have found that CMA blockade leads to impaired visual function, mainly cone-dependent. Conversely, mice that overexpress LAMP-2A show higher resistance to chemically-induced photoreceptor damage.
Conclusions :
Overall, our results support a cytoprotective role for CMA in retina, which becomes essential under conditions, such as aging, when the activity of other autophagic pathways declines, and also highlight the feasibility of upregulating CMA against retinal degeneration.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.