Abstract
Purpose :
Defective autophagy, a cellular mechanism to recycle cellular components and eliminate altered proteins, has been linked to neurodegenerative diseases. Selective forsm of autophagy, such as chaperone-mediated autophagy (CMA), contribute to normal turnover of prone-to-aggregate proteins such as α-synuclein or tau. The gradual decline of CMA with age is in part responsible for the proteotoxicity observed in the aging tissues and has an aggravating effect on age-related neurodegenerative conditions such as Parkinson’s and Alzheimer’s diseases. Since we have identified a similar degenerative phenotype in retinas of animals with compromised CMA, we set to test the possible protective effects of chemical upregulation of CMA in different models of retinal degeneration.
Methods :
We have used first-in-class novel compounds capable to activate CMA and optimized for in vivo delivery and monitored changes in degeneration features in in different mouse models of retinal degeneration.
Results :
Here, we show data supporting improved histophatology and retinal function upon administration of the CMA modulators in the context of MNU-induced photoreceptor degeneration and in the rd10 mouse model of retinitis pigmentosa.
Conclusions :
CMA activating compounds could represent a novel therapeutic venue to treat retinal and other degenerative diseases of aging by preventing or reverting the age-dependent functional decline of this component of the proteostasis network.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.