Abstract
The most common Rhodopsin (Rh) mutation associated with autosomal dominant retinitis pigmentosa (ADRP) in North America is the substitution of proline 23 by histidine (RhP23H). Unlike the wild-type Rh, mutant RhP23H exhibits folding defects and forms intracellular aggregates. The mechanisms responsible for the recognition and clearance of misfolded RhP23H and their relevance to photoreceptor neuron (PN) degeneration are poorly understood. Folding-deficient membrane proteins are subjected to Endoplasmic Reticulum (ER) quality control, and we have recently shown that RhP23H is a substrate of the ER–associated degradation (ERAD) effector VCP/ter94, a chaperone that extracts misfolded proteins from the ER (a process called retrotranslocation) and facilitates their proteasomal degradation. Here, we used Drosophila, in which Rh1P37H (the equivalent of mammalian RhP23H) is expressed in PNs, and found that the endogenous Rh1 is required for Rh1P37H toxicity. Genetic inactivation of VCP increased the levels of misfolded Rh1P37H and further activated the Ire1/Xbp1 ER stress pathway in the Rh1P37H retina. Despite this, Rh1P37H flies with decreased VCP function displayed a potent suppression of retinal degeneration and blindness, indicating that VCP activity promotes neurodegeneration in the Rh1P37H retina. Pharmacological treatment of Rh1P37H flies with the VCP/ERAD inhibitor Eeyarestatin I or with the proteasome inhibitor MG132 also led to a strong suppression of retinal degeneration. Collectively, our findings raise the possibility that excessive retrotranslocation and/or degradation of visual pigment is a primary cause of PN degeneration.
Highlights
Collapse of protein homeostasis due to protein misfolding and aggregation is the central pathogenic event in neurodegenerative disease [1]
Patients affected by autosomal dominant retinitis pigmentosa (ADRP) experience gradual loss of vision, and mutations in the visual pigment Rhodopsin—a G protein-coupled receptor that mediates phototransduction— are associated with ADRP
It is currently unclear how mutant RhP23H leads to photoreceptor neuron (PN) degeneration in ADRP
Summary
Collapse of protein homeostasis (proteostasis) due to protein misfolding and aggregation is the central pathogenic event in neurodegenerative disease [1]. Rh is a G protein-coupled receptor that initiates the phototransduction cascade and more than 120 Rh point mutations have been associated with RP; most of these Rh mutations act dominantly to cause autosomal dominant RP (ADRP), while some mutations cause recessive RP [7]. Based on their biochemical and cellular properties, Rh mutations have been grouped into several classes [7]. Substitution of proline 23 by histidine (RhP23H) is the most common genetic defect associated with ADRP in North America and is arguably the best characterized Rh mutation to date [3,7,8]. Unlike wild-type (WT) Rh, which is properly delivered to the plasma membrane, mutant RhP23H fails to fold properly [3,5,9,10], appears to exhibit enhanced retention within the endoplasmic reticulum (ER) [3,5,7,11,12,13] and forms intracellular aggregates [14,15,16]
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