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.

Changes in endolysosomal organization define a pre-degenerative state in thecrumbsmutantDrosophilaretina

“…Second, loss of crb induces an upregulation of NADPH-oxidase activity, resulting in higher levels of reactive oxygen species (ROS) [30]. Elevated ROS levels play a critical role in the pathogenesis of many neurodegenerative diseases, including retinal degeneration [59][60][61][62]. There is increasing evidence suggesting a crucial role of ROS in activating autophagy, one of the main degradative pathways critical not only for neuronal health, but also for the survival of other cells, e. g. muscles [60,63].…”

“…Elevated ROS levels play a critical role in the pathogenesis of many neurodegenerative diseases, including retinal degeneration [59][60][61][62]. There is increasing evidence suggesting a crucial role of ROS in activating autophagy, one of the main degradative pathways critical not only for neuronal health, but also for the survival of other cells, e. g. muscles [60,63]. During autophagy, engulfed organelles, nutrients, and protein aggregates are delivered to the lysosome to be broken down and degraded or eventually recycled [64][65][66][67].…”

The Relevance of Oxidative Stress in the Pathogenesis and Therapy of Retinal Dystrophies

“…Moreover, photoreceptor cells are localized near arteries due to their high demand of oxygen, but upon photoreceptor death, consumption in the retina decreases. Blood circulation in the choroidal vessels does not adapt to this decrease and thus, the consequent hyperoxia could cause oxidative damage [35].…”

“…Nonetheless, in response to different stimuli and cellular contexts, autophagy can also modulate cell viability, either enhancing cell survival or cell death. Autophagy is involved in a number of different processes in the retina participating in development and tissue remodeling and it is also implicated in photoreceptor cell death in response to calcium cytotoxicity, structural damage, and oxidative stress [35,47]. On the other hand, the aged retina is characterized by increased levels of reactive oxygen species (ROS), impaired autophagy, excessive energy consumption, and DNA damage, all of which contribute to the degeneration of RPE cells and link to AMD pathogenesis [48,49].…”

“…Some studies suggest that autophagy could have beneficial effects in RP while others indicate it could negatively affect photoreceptor death. This apparent contradiction may be reconciled if we consider that: (i) RP is a highly heterogenous genetic disease, with many different genes and mutations associated to this disorder, therefore the importance of autophagy in retinal cells might be different depending on the mutation; (ii) autophagy may play different roles in the death of rods and cones; and finally (iii) moderate levels of autophagy in the photoreceptors may be beneficial whereas excessive autophagy may be deleterious [35]. Again, a delicate balance between autophagy promotion or reduction depending on the cell requirements, the intensity and time duration of the stress stimulus may be the clue to understand the relevance of this pathway in retinal homeostasis, particularly when retinal cells are already under distress by genetic mutations.…”