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  • Pharmacological Inhibition of the VCP/Proteasome Axis Rescues Photoreceptor Degeneration in RHOP23H Rat Retinal Explants.

Pharmacological Inhibition of the VCP/Proteasome Axis Rescues Photoreceptor Degeneration in RHOP23H Rat Retinal Explants.

Biomolecules (2021-10-24)
Merve Sen, Oksana Kutsyr, Bowen Cao, Sylvia Bolz, Blanca Arango-Gonzalez, Marius Ueffing
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). Overload of these degradation processes for a prolonged period leads to imbalanced proteostasis and may eventually result in cell death. ERAD of misfolded proteins, such as 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-Rhodopsin Antibody, clone RET-P1, clone RET-P1, Chemicon®, from mouse
Sigma-Aldrich
Monoclonal Anti-Glial Fibrillary Acidic Protein (GFAP) antibody produced in mouse, clone G-A-5, ascites fluid
Sigma-Aldrich
Kifunensine, Kitasatosporia kifunense, A potent alkaloid inhibitor of mannosidase I.
Sigma-Aldrich
Anti-Cone Arrestin Antibody, Chemicon®, from rabbit
Roche
In Situ Cell Death Detection Kit, Fluorescein, sufficient for ≤50 tests, suitable for detection