Inhibition of mTOR signaling by rapamycin protects photoreceptors from degeneration in <i>rd1</i> mice
Jialiang Yang, 电子科技大学附属四川省人民医院人类疾病基因四川省重点实验室，四川 成都 610072，中国, Tongdan Zou, Fang Yang, Zhenglin Yang, Houbin Zhang, 中国科学院四川省转化医学医院，成都生物研究所，四川 成都 610072，中国, 中国医学科学院防盲研究中心，四川省医学科学院四川省人民医院，四川 成都 610072，中国
Abstract
Retinitis pigmentosa (RP) is an inherited retinal degenerative disease that begins with defective rod photoreceptor function, followed by impaired cone function, and complete blindness in its late stage. To date, however, there is no effective treatment for RP. By carrying a nonsense mutation in the <i>Pde6b</i> gene, <i>rd1</i> mice display elevated cGMP in conjunction with higher intracellular Ca<sup>2+</sup> in their rod photoreceptors, resulting in fast retinal degeneration. Ca<sup>2+</sup> has been linked to activation of the mammalian target of rapamycin (mTOR) pathway. The mTOR pathway integrates extracellular and intracellular signals to sense the supply of nutrients and plays a central role in regulating protein and lipid synthesis as well as apoptosis and autophagy. In the present study, we showed that mTOR and phosphorylated mTOR (p-mTOR, activated form of mTOR) are up-regulated in <i>rd1</i> photoreceptors at postnatal day 10 (P10), a pre-degenerative stage. Moreover, the downstream effectors of mTOR, such as pS6K and S6K, are also increased, suggesting activation of the mTOR signaling pathway. Intravitreal administration of rapamycin, a negative regulator of mTOR, inhibits the mTOR pathway in <i>rd1</i> photoreceptors. Consequently, the progression of retinal degeneration is slower and retinal function is enhanced, possibly mediated by activation of autophagy in the photoreceptors. Taken together, these results highlight rapamycin as a potential therapeutic avenue for retinal degeneration.