Shifting the balance of autophagy and proteasome activation reduces proteotoxic cell death: a novel therapeutic approach for restoring photoreceptor homeostasis

Abstract

The P23H variant of rhodopsin results in misfolding of the protein, and is a common cause of the blinding disease autosomal dominant retinitis pigmentosa (adRP). We have recently demonstrated that degeneration of photoreceptor cells in retinas of P23H mice is due to the endoplasmic reticulum stress (ERS)-induced activation of autophagy that leads to a secondary proteasome insufficiency and activation of cell death pathways. We propose that this increased level of autophagy flux relative to proteasome activity, which we term the A:P ratio, represents a marker of altered photoreceptor cell homeostasis, and that therapies aimed at normalizing this ratio will result in increased photoreceptor cell survival. To test this postulate, we treated P23H mice with a chemical chaperone (4-phenylbutyric acid) to improve rhodopsin folding, or with a selective phosphodiesterase-4 inhibitor (rolipram) to increase proteasome activity. P23H mice treated with either of these agents exhibited reduced ERS, decreased autophagy flux, increased proteasome activity, and decreased activation of cell death pathways. In addition, rates of retinal degeneration were decreased, and photoreceptor morphology and visual function were preserved. These findings support the conclusion that normalizing the A:P ratio, either by reducing the ERS-induced activation of autophagy, or by increasing proteasome activity, improves photoreceptor survival, and suggest a potential new therapeutic strategy for the treatment of adRP caused by protein folding defects.

Mechanisms of Photoreceptor Death in Retinitis Pigmentosa

“…However, when damage is severe, autophagy can lead to apoptotic cell death; indeed, many regulators of autophagy pathways also have central roles in regulating apoptosis [ 34 ]. Autophagy has been associated with photoreceptor death in RP models in many different studies [ 35 , 36 , 37 , 38 ], but the precise role of this pathway remains controversial. As discussed later in this review, increased autophagy flux (the dynamic process of autophagy) appears to be protective in some animal models of RP while other studies have suggested autophagy reduces photoreceptor survival [ 22 , 35 , 36 ].…”

“…Yao et al therefore suggest that decreasing autophagy shifts degradation of mis-folded P23H rhodopsin towards the proteasome and this may reduce the ER retention of mutant protein, thus improving cell survival. In a subsequent study, this group showed that reducing protein mis-folding by treatment with the chaperone 4-PBA reduces ER stress and decreases autophagy activation, resulting in reduced degradation of proteasome subunits and hence restoring proteasome activity [ 37 ]. This was accompanied by improved visual function and reduced photoreceptor death.…”

Endoplasmic reticulum stress and the protein degradation system in ophthalmic diseases

“…In addition, it was reported that inhibition of autophagy, especially in the case of adequate nutrition, can enhance the activity of proteasomes, which are activated as a compensatory form of protein degradation (Wang et al, 2013). Moreover, Zacks et al reported that in a mouse model of retinal degeneration caused by a gene mutation in P23H rhodopsin, ER stress-related autophagy led to photoreceptor death, while the treatment of P23H mice with selective phosphodiesterase-4 inhibitor (rolipram) to increase proteasome activity could effectively inhibit ER stressrelated autophagy and reduce the rate of retinal degeneration (Qiu et al, 2019). Therefore, the balance between UPS and autophagy is very important, and these two systems have irreplaceable effects on cellular health.…”

Peer Review #3 of "Endoplasmic reticulum stress and the protein degradation system in ophthalmic diseases (v0.1)"

“…Manuscript to be reviewed addition, it was reported that inhibition of autophagy, especially in the case of adequate nutrition, can enhance the activity of proteasomes, which are activated as a compensatory form of protein degradation (Wang et al 2013). Moreover, Zacks et al reported that in a mouse model of retinal degeneration caused by a gene mutation in P23H rhodopsin, ER stress-related autophagy led to photoreceptor death, while the treatment of P23H mice with selective phosphodiesterase-4 inhibitor (rolipram) to increase proteasome activity could effectively inhibit ER stress-related autophagy and reduce the rate of retinal degeneration (Qiu et al 2019). Therefore, the balance between UPS and autophagy is very important, and these two systems have irreplaceable effects on cellular health.…”