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Cited by 78Retinal Development and DisordersEndoplasmic Reticulum Stress and DiseaseHeat shock proteins research

Inactivation of VCP/ter94 Suppresses Retinal Pathology Caused by Misfolded Rhodopsin in Drosophila

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Griciuc, Ana, Aron, Liviu, Roux, Michel J., Klein, Rüdiger, Giangrande, Angela, Ueffing, Marius·2010·PLoS Genetics
DOI 10.1371/journal.pgen.1001075PMC PMC2928793
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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 (Rh(P23H)). Unlike the wild-type Rh, mutant Rh(P23H) exhibits folding defects and forms intracellular aggregates. The mechanisms responsible for the recognition and clearance of misfolded Rh(P23H) 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 Rh(P23H) 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 Rh1(P37H) (the equivalent of mammalian Rh(P23H)) is expressed in PNs, and found that the endogenous Rh1 is required for Rh1(P37H) toxicity. Genetic inactivation of VCP increased the levels of misfolded Rh1(P37H) and further activated the Ire1/Xbp1 ER stress pathway in the Rh1(P37H) retina. Despite this, Rh1(P37H) flies with decreased VCP function displayed a potent suppression of retinal degeneration and blindness, indicating that VCP activity promotes neurodegeneration in the Rh1(P37H) retina. Pharmacological treatment of Rh1(P37H) 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.

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Authors
Griciuc, A., Aron, L., Roux, M. J., Klein, R., Giangrande, A., & Ueffing, M.
Affiliations
  • Helmholtz Munich (DE)
  • Max Planck Institute of Neurobiology (DE)
  • Centre National de la Recherche Scientifique (FR)
Corresponding author
  • Aron, Liviu
  • Ueffing, Marius
ORCID
Venue
PLoS Genetics
Publisher
Public Library of Science (PLoS)
Published
2010-08-26
Volume
6
Issue
8
Pages
e1001075
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
DOI
10.1371/journal.pgen.1001075
PMC
PMC2928793
OpenAlex
W1992298511
Cited by
78
References
4
Citations by year
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FWCI
2.87
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Genetics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Max Planck Institute for Plasma Physics (submittedVersion)
  • Max Planck Digital Library (submittedVersion, other-oa)
  • Figshare (submittedVersion, cc-by)
  • Site cant be reached (submittedVersion, cc-by)
  • MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
Keywords
autosomal dominant retinitis pigmentosa, photoreceptor degeneration, ER-associated degradation, retrotranslocation, ER quality control, proteasome inhibition
MeSH terms
Valosin Containing Protein, Adenosine Triphosphatases, Animals, Disease Models, Animal, Drosophila, Endoplasmic Reticulum, Female, Humans, Male, Retina, Retinitis Pigmentosa, Rhodopsin, Down-Regulation, Protein Folding, Cell Cycle Proteins, Mutation, Missense, Gene Silencing, Drosophila Proteins

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