Pharmacological modulation of the retinal unfolded protein response in Bardet-Biedl syndrome reduces apoptosis and preserves light detection ability

A. Mockel, C. Obringer, T.B. Hakvoort, M. Seeliger, W.H. Lamers, C. Stoetzel, H. Dollfus, V. Marion

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16 Citations (Scopus)

Abstract

Ciliopathies, a class of rare genetic disorders, present often with retinal degeneration caused by protein transport defects between the inner segment and the outer segment of the photoreceptors. Bardet-Biedl syndrome is one such ciliopathy, genetically heterogeneous with 17 BBS genes identified to date, presenting early onset retinitis pigmentosa. By investigating BBS12-deprived retinal explants and the Bbs12(-/-) murine model, we show that the impaired intraciliary transport results in protein retention in the endoplasmic reticulum. The protein overload activates a proapoptotic unfolded protein response leading to a specific Caspase12-mediated death of the photoreceptors. Having identified a therapeutic window in the early postnatal retinal development and through optimized pharmacological modulation of the unfolded protein response, combining three specific compounds, namely valproic acid, guanabenz, and a specific Caspase12 inhibitor, achieved efficient photoreceptor protection, thereby maintaining light detection ability in vivo.
Original languageEnglish
Pages (from-to)37483-37494
Number of pages12
JournalJournal of Biological Chemistry
Volume287
Issue number44
DOIs
Publication statusPublished - 26 Oct 2012

Keywords

  • ENDOPLASMIC-RETICULUM STRESS
  • INITIATION-FACTOR 2-ALPHA
  • RETINITIS-PIGMENTOSA
  • VALPROIC ACID
  • MOUSE MODEL
  • ER STRESS
  • TRANSCRIPTION FACTOR
  • MESSENGER-RNA
  • CILIA DEFECTS
  • CELL FATE

Cite this

Mockel, A., Obringer, C., Hakvoort, T. B., Seeliger, M., Lamers, W. H., Stoetzel, C., Dollfus, H., & Marion, V. (2012). Pharmacological modulation of the retinal unfolded protein response in Bardet-Biedl syndrome reduces apoptosis and preserves light detection ability. Journal of Biological Chemistry, 287(44), 37483-37494. https://doi.org/10.1074/jbc.M112.386821