Disease mechanisms and neuroprotection by tauroursodeoxycholic acid in Rpgr knockout mice

Xun Zhang, Uma Shahani, James Reilly, Xinhua Shu*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Mutations in the RPGR gene are the predominant cause of retinitis pigmentosa (RP). RPGR plays a critical role as a scaffold protein in the regulation of protein trafficking from the basal body to the axoneme, where the cargoes are transported to the outer segments (OS) of photoreceptors. This trafficking process is controlled directly by intraflagellar transport (IFT) complexes and regulated by the RPGR protein complex, although the precise mechanisms have yet to be defined. We employed an Rpgr conditional knockout (cko) mouse model to investigate the disease mechanisms during retinal degeneration and to evaluate the protective effects of tauroursodeoxycholic acid (TUDCA). Rhodopsin, cone opsins and transducin were mislocalized in Rpgr cko photoreceptors, while localization of NPHP4 to connecting cilia was absent, suggesting that RPGR is required for ciliary protein trafficking. Microglia were activated in advance of retinal degeneration in Rpgr cko mouse retinas. TUDCA treatment suppressed microglial activation and inflammation and prevented photoreceptor degeneration in Rpgr cko mice. Our data demonstrated that TUDCA has therapeutic potential for RPGR-associated RP patients.
Original languageEnglish
Pages (from-to)18801-18812
Number of pages12
JournalJournal of Cellular Physiology
Volume234
Issue number10
Early online date28 Mar 2019
DOIs
Publication statusPublished - 29 Jun 2019

Keywords

  • retinitis pigmentosa
  • RPGR
  • microglia activation
  • tauroursodeoxycholic acid
  • neuroprotection

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