PGC-1α and PPARs cooperatively mediate photoreceptor neuroprotection in rd1 mouse inherited retinal degeneration

Abstract

Retinitis pigmentosa (RP) is a group of inherited diseases characterized by a primary rod photoreceptor dysfunction and progressive rod and cone cell death. Due to their very high energy demand, the degeneration of photoreceptors may be linked to insufficient energy supply or metabolic imbalance. Critical transcription factors that regulate metabolism such as peroxisome proliferator-activated receptors (PPARs) and their co-activator PGC-1 have been found to play important roles in neurodegenerative diseases, but their potential roles in RP have yet not been disclosed. In this study, we used organotypic retinal explant cultures derived from the rd1 mouse model for RP to investigate the effects of PPAR, PPAR{gamma}, PPAR{beta}/{delta} agonists, as well as PGC-1 activation and inhibition. Photoreceptor death in the outer nuclear layer (ONL) of the retina was quantified using the TUNEL assay, while in situ activity assays were used to monitor effects of PPARs and PGC-1 on poly (ADP-ribose) polymerase (PARP) and calpain activity. In addition, we performed immunostainings to evaluate poly (ADP-ribose) (PAR) generation and activation of calpain-1 and calpain-2. We found that PPAR{beta}/{delta} agonists had limited effects, while activation of PPAR, PPAR{gamma}, and PGC-1 significantly reduced photoreceptor death and PARP activity in rd1 retina. Conversely, inhibition of PGC-1 had a strong detrimental effect on photoreceptor viability. Activation of the histone deacetylase sirtuin-1, an upstream agonist of PGC-1, had no effect unless it was combined with simultaneous inhibition of PARP. Furthermore, PPAR{gamma} and PGC-1 effectively suppressed overall calpain activity and overactivation of calpain-2, alleviating photoreceptor degeneration caused by Ca2+ imbalance. In summary, our data supports the concept of a PARP-sirtuin-1-PGC-1-PPAR-PARP feedback control that connects defective energy metabolism to photoreceptor degeneration. Specifically, our findings suggest that PPAR, PPAR{gamma}, and PGC-1 cooperate to preserve photoreceptor viability, highlighting PPAR-signaling as a promising target for future therapeutic interventions.