Pharmacological inhibition of the VCP/proteasome axis rescues photoreceptor degeneration in RHO^P23H rat retinal explants

Abstract

Rhodopsin (RHO) misfolding mutations are a common cause of the blinding disease autosomal dominant retinitis pigmentosa (adRP). The most prevalent mutation, RHOP23H, results in its misfolding and retention in the Endoplasmic Reticulum (ER). Under homeostatic conditions, misfolded proteins are selectively identified, retained at the ER, and cleared via ER-associated degradation (ERAD) and/or autophagy. Overload of these degradation processes for a prolonged period leads to imbalanced proteostasis and may eventually result in cell death. ERAD of misfolded proteins like RHOP23H includes the subsequent steps of protein recognition, targeting for ERAD, retrotranslocation, and proteasomal degradation. In the present study, we investigated and compared pharmacological modulation of ERAD at these four different major steps. We show that inhibition of the VCP/proteasome activity favors cell survival and suppresses P23H-mediated retinal degeneration in RHOP23H rat retinal explants. We suggest targeting this activity as a therapeutic approach for patients with currently untreatable adRP.

Rodent Models of Retinal Degeneration: From Purified Cells in Culture to Living Animals

“…For instance, phosphodiesterase blockers were applied to model photoreceptor degeneration (Vallazza-Deschamps et al, 2005) whereas retinal ganglion cell loss was induced by application of a glutamate receptor agonist, MK801 (Froger et al, 2013). Retinas from various animal models of photoreceptor degeneration (e.g., rd1, P23H Rhodopsin) were also used in such studies to screen for neuroprotective molecules because these explants bypass all problems of molecule bioavailability that may exist in-vivo via application directly in the culture medium (Vallazza-Deschamps et al, 2005;Sen et al, 2021a;Sen et al, 2021b). Reverse magnetofection was even applied to deliver siRNA in rodent retinal explant (Bassetto et al, 2021).…”