UCL  IRIS
Institutional Research Information Service
UCL Logo
Please report any queries concerning the funding data grouped in the sections named "Externally Awarded" or "Internally Disbursed" (shown on the profile page) to your Research Finance Administrator. Your can find your Research Finance Administrator at http://www.ucl.ac.uk/finance/research/post_award/post_award_contacts.php by entering your department
Please report any queries concerning the student data shown on the profile page to:

Email: portico-services@ucl.ac.uk

Help Desk: http://www.ucl.ac.uk/ras/portico/helpdesk
Publication Detail
Hsp90 inhibition protects against inherited retinal degeneration.
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Article
  • Authors:
    AguilĂ  M, Bevilacqua D, McCulley C, Schwarz N, Athanasiou D, Kanuga N, Novoselov SS, Lange CA, Ali RR, Bainbridge JW, Gias C, Coffey PJ, Garriga P, Cheetham ME
  • Publisher:
    Oxford University Press (OUP)
  • Publication date:
    15/04/2014
  • Journal:
    Human Molecular Genetics
  • Print ISSN:
    0964-6906
  • PII:
    ddt613
  • Language:
    ENG
  • Addresses:
    Department of Ocular Biology and Therapeutics, UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK.
Abstract
The molecular chaperone Hsp90 is important for the functional maturation of many client proteins, and inhibitors are in clinical trials for multiple indications in cancer. Hsp90 inhibition activates the heat shock response and can improve viability in a cell model of the P23H misfolding mutation in rhodopsin that causes autosomal dominant retinitis pigmentosa (adRP). Here, we show that a single low dose of the Hsp90 inhibitor HSP990 enhanced visual function and delayed photoreceptor degeneration in a P23H transgenic rat model. This was associated with the induction of heat shock protein expression and reduced rhodopsin aggregation. We then investigated the effect of Hsp90 inhibition on a different type of rod opsin mutant, R135 L, which is hyperphosphorylated, binds arrestin and disrupts vesicular traffic. Hsp90 inhibition with 17-AAG reduced the intracellular accumulation of R135 L and abolished arrestin binding in cells. Hsf1(-/-) cells revealed that the effect of 17-AAG on P23H aggregation was dependent on HSF-1, whereas the effect on R135 L was HSF-1 independent. Instead, the effect on R135 L was mediated by a requirement of Hsp90 for rhodopsin kinase (GRK1) maturation and function. Importantly, Hsp90 inhibition restored R135 L rod opsin localization to WT phenotype in vivo in rat retina. Prolonged Hsp90 inhibition with HSP990 in vivo led to a post-translational reduction in GRK1 and phosphodiesterase (PDE6) protein levels, identifying them as Hsp90 clients. These data suggest that Hsp90 represents a potential therapeutic target for different types of rhodopsin adRP through distinct mechanisms, but also indicate that sustained Hsp90 inhibition might adversely affect visual function.
Publication data is maintained in RPS. Visit https://rps.ucl.ac.uk
 More search options
UCL Researchers
Author
Institute of Ophthalmology
Author
Department of Neuromuscular Diseases
University College London - Gower Street - London - WC1E 6BT Tel:+44 (0)20 7679 2000

© UCL 1999–2011

Search by