Poly ADP ribosylation and extracellular vesicle activity in rod photoreceptor degeneration

Abstract

Retinitis Pigmentosa is a group of inherited neurodegenerative diseases that result in selective cell death of photoreceptors. In the developed world, RP is regarded as the main cause of blindness among the working age population. The precise mechanisms eventually leading to cell death remain unknown and to date no adequate treatment for RP is available. Poly ADP ribose polymerase (PARP) over activity is involved in photoreceptor degeneration and pharmacological inhibition or genetic knock-down PARP1 activity protect photoreceptors in mice models, the mechanism of neuroprotection is not clear yet. Our result indicated that olaparib, a PARP1 inhibitor, significantly rescued photoreceptor cells in rd10 retina. Extracellular vesicles (EVs) were previously recognized as a mechanism for discharging useless cellular components. Growing evidence has elucidated their roles in cell–cell communication by carrying nucleic acids, proteins and lipids that can, in turn, regulate behavior of the target cells. Recent research suggested that EVs extensively participate in progression of diverse blinding diseases, such as age-related macular (AMD) degeneration. Our study demonstrates the involvement of EVs activity in the process of photoreceptor degeneration in a PDE6 mutation. PARP inhibition protects photoreceptors via regulation of the EVs activity in rod photoreceptor degeneration in a PDE6b mutation.

Small-Medium Extracellular Vesicles and Their miRNA Cargo in Retinal Health and Degeneration: Mediators of Homeostasis, and Vehicles for Targeted Gene Therapy

“…Previous studies by Vidal-Gil et al (2019) report that the exosome protein marker CD9 was localized to the photoreceptor inner segments and ONL, further supporting a photoreceptor-origin hypothesis. However, it should be noted that CD9 was also found in the INL, GCL and choroid.…”

“…However, it should be noted that CD9 was also found in the INL, GCL and choroid. Using a genetic model ( rd10 mice) of retinitis pigmentosa, which results in progressive rod photoreceptor-specific cell death ( Gargini et al, 2007 ; Vidal-Gil et al, 2019 ) showed that EVs isolated from retinal explants contain rhodopsin protein. This exosomal rhodopsin expression increased following photoreceptor rescue.…”

“…Exosomes, the smallest EV fraction (40–200 nm in diameter) ( Théry et al, 2002 ; Vella et al, 2017 ; Hessvik and Llorente, 2018 ; Słomka et al, 2018 ), in particular, have recently been implicated in the pathogenesis of retinal degenerative diseases. These include Age-Related Macular Degeneration (AMD) ( Wang et al, 2009 ; Klingeborn et al, 2017 ; Hsu et al, 2018 ; Li et al, 2019 ), Diabetic Retinopathy ( Huang et al, 2018 ), and Retinitis Pigmentosa ( Vidal-Gil et al, 2019 ).…”

RPE Cells Engulf Microvesicles Secreted by Degenerating Rod Photoreceptors

“…This vesicle release is potentially a method to remove unwanted proteins during photoreceptor degeneration, when OS phagocytosis is compromised due to reduced OS transport of rhodopsin. Recent studies indicate that microvesicles are means of intercellular communication (Lee and Kim, 2017;Vidal-Gil et al, 2019). Contents of microvesicles, such as miRNA and signaling proteins, mediate phenotypic changes of the recipient cells (Schorey and Harding, 2016;Roballo et al, 2019).…”

Curcumin as a Therapeutic Option in Retinal Diseases

“…Retinitis pigmentosa (RP) is the most frequent hereditary retinal degenerative disorder in adults [68]. It causes a progressive loss of rod photoreceptors followed by a loss of cones [69].…”