PGC-1α and PPARs cooperatively mediate photoreceptor neuroprotection in rd1 mouse inherited retinal degeneration
TL;DR
The data support the concept of a PARP–sirtuin-1–PGC-1α–PPAR–PARP feedback control that connects defective energy metabolism to photoreceptor degeneration and highlights PPAR-signaling as a promising target for future therapeutic interventions.
Abstract
Retinitis pigmentosa (RP) is a group of inherited diseases characterized by primary rod photoreceptor dysfunction and progressive 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 PPAR gamma coactivator 1α (PGC-1α), have been found to play important roles in neurodegenerative diseases, but their potential roles in RP have yet not been elucidated. Here, organotypic retinal explant cultures derived from retinal degeneration 1 (rd1) mice were used to investigate the effects of PPARα, PPARγ, PPARβ/δ agonists, as well as PGC-1α activation and inhibition. Photoreceptor death was quantified using the TUNEL assay, while in situ activity assays were used to monitor effects of PPARs and PGC-1α on poly (ADP-ribose) polymerase (PARP) and calpain activity. Generation of poly (ADP-ribose) (PAR) and activation of calpain-1 and calpain-2 were evaluated by immunostaining. PGC-1α/PPAR-associated transcriptional changes were assessed by RT-qPCR. We found that PPARβ/δ agonists had limited effects, while treatment targeting PPARα, PPARγ, and PGC-1α significantly reduced photoreceptor death and PARP activity in rd1 retina. RT-qPCR analysis in treated rd1 retina confirmed upregulation of genes downstream of PGC-1α/PPAR signaling. Stimulation of the histone deacetylase sirtuin-1, an upstream regulator of PGC-1α, had no beneficial effect on photoreceptor viability unless combined with PARP inhibition. Furthermore, PPARγ and PGC-1α effectively suppressed overall calpain activity and overactivation of calpain-2, alleviating photoreceptor degeneration caused by Ca2+ imbalance. In summary, our data support the concept of a PARP–sirtuin-1–PGC-1α–PPAR–PARP feedback control that connects defective energy metabolism to photoreceptor degeneration. Specifically, our findings suggest that PPARα, PPARγ, and PGC-1α cooperate to preserve photoreceptor viability, highlighting PPAR-signaling as a promising target for future therapeutic interventions.