MTORC1 Activation in Chx10-Specific Tsc1 Knockout Mice Accelerates Retina Aging and Degeneration

ABSTRACT: Age-associated decline in retina function is largely responsible for the irreversible vision deterioration in the elderly population. It is also an important risk factor for the development of degenerative and angiogenic diseases. However, the molecular mechanisms involved in the process of aging in the retina remain largely elusive. This study investigated the role of mTORC1 signaling in aging of the retina. We showed that mTORC1 was activated in old-aged retina, particularly in the ganglion cells. The role of mTORC1 activation was further investigated in Chx10-Cre;Tsc1fx/fx mouse (Tsc1-cKO). Activation of mTORC1 was found in bipolar and some of the ganglion and amacrine cells in the adult Tsc1-cKO retina. Bipolar cell hypertrophy and Müller gliosis were observed in Tsc1-cKO since 6 weeks of age. The abnormal endings of bipolar cell dendritic tips at the outer nuclear layer resembled that of the old-aged mice. Microglial cell activation became evident in 6-week-old Tsc1-cKO. At 5 months, the Tsc1-cKO mice exhibited advanced features of old-aged retina, including the expression of p16Ink4a and p21, expression of SA-β-gal in ganglion cells, decreased photoreceptor cell numbers, decreased electroretinogram responses, increased oxidative stress, microglial cell activation, and increased expression of immune and inflammatory genes. Inhibition of microglial cells by minocycline partially prevented photoreceptor cell loss and restored the electroretinogram responses. Collectively, our study showed that the activation of mTORC1 signaling accelerated aging of the retina by both cell autonomous and nonautonomous mechanisms. Our study also highlighted the role of microglia cells in driving the decline in retina function.

SUBMITTER: Rao Y 

PROVIDER: S-EPMC8589503 | biostudies-literature |

REPOSITORIES: biostudies-literature