Tsc2 knockout counteracts ubiquitin-proteasome system insufficiency and delays photoreceptor loss in retinitis pigmentosa

Methods to stimulate protein degradation through the ubiquitin-proteasome system (UPS) are being investigated as approaches to treat multiple human diseases and delay aging. Recent studies highlighted a nontrivial relationship between the mammalian target of rapamycin complex 1 (mTORC1) pathway and the UPS. In different experimental models, both activation and inhibition of the mTORC1 pathway were reported to stimulate degradation of ubiquitinated proteins and proteasomal abundance. Here, we show that in rod photoreceptors, activation of mTORC1 through deletion of its negative regulator tuberous sclerosis complex protein 2 (Tsc2) counteracts UPS insufficiency, increases proteasomal activity, improves photoreceptor survival, and delays vision loss in a mouse model of human blindness caused by a misfolded protein. We show that an observed mTORC1-mediated increase in proteasomal activity was reduced by phosphatase treatment and could not be attributed to the change in proteasomal abundance. Our study indicates that chronic mTORC1 activation in vivo could stimulate the UPS in degenerating photoreceptor neurons. Further studies to understand changes in the degradation of ubiquitinated proteins and the modulation of UPS through phosphorylation under chronic mTORC1 activation might aid in the development of therapeutic approaches to diseases linked to impaired proteasomal degradation.