Autophagy Dysfunction and Oxidative Stress, Two Related Mechanisms Implicated in Retinitis Pigmentosa

Abstract

Retinitis pigmentosa (RP) is one of the most common clinical subtypes of retinal degeneration (RD), and it is a neurodegenerative disease that could cause complete blindness in humans because it ultimately affects the photoreceptors viability. RP afflicts an estimated 1.5 million patients worldwide. The retina is highly susceptible to oxidative stress which can impair mitochondrial function. Many retina pathologies, such as diabetic retinopathy and secondary cone photoreceptor death in RP, have been related directly or indirectly with mitochondrial dysfunction. The possible role of autophagy in retina and cell differentiation is described and also the implications of autophagy dysregulation in RP. The present review shows the crucial role of autophagy in maintaining the retina homeostasis and possible therapeutic approaches for the treatment of RP.

Keywords: autophagy; eye diseases; mitochondrion; oxidative stress; retinitis pigmentosa.

FIGURE 1

Molecular mechanisms describing the autophagy process that occur in the retinal pigment epithelium. Phosphatidylinositol-3-kinase-I (PI3K-I) is activated and this leads to the activation of the mechanistic target of Rapamycin (mTOR) triggering the dissociation of the serine/threonine-protein kinase complex (ULKc) that binds to the endoplasmic reticulum (ER). Subsequently, PI3K-III complex is activated and forms the phosphatidylinositol 3-phosphate (PI3P) pool in the rough ER. The Double FYVE-containing protein 1 (DFCP1) recognizes the new synthetized PI3P and forms the omegasome with the help of the ER. The WD repeat domain phosphoinositide-interacting protein 2 (WIPI-2) localizes to the omegasome-anchored phagophores. Then, Atg7 or E1 like (activation enzyme) together with Atg10 or E2 conjugation like enzyme activates the union of Atg5 and Atg12 (Atg5-Atg12) with Atg16. Atg7 also activates light chain 3-I (LC3-I) or Atg3, that forms LC3-II, also called Atg8 or LC3-phosphatidyl ethanolamine (LC3-PE). LC3-II gets inserted into the phagophore through the union to Atg5. Later on, P62 links ubiquitinated proteins or mitochondria to LC3 and the phagopore. Finally, the autophagosome formed, fuses with the lysosome to form the autolysosome.