Disease mechanisms and neuroprotection by tauroursodeoxycholic acid in Rpgr knockout mice

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
JournalJournal of Cellular Physiology
DOIs
Publication statusPublished - 28 Mar 2019

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Knockout Mice
Retinal Degeneration
Retinitis Pigmentosa
Protein Transport
Cone Opsins
Transducin
Basal Bodies
Axoneme
Proteins
Rhodopsin
Cilia
Microglia
Retina
Scaffolds
Inflammation
Mutation
Genes
Chemical activation
Therapeutics
Neuroprotection

Keywords

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

Cite this

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title = "Disease mechanisms and neuroprotection by tauroursodeoxycholic acid in Rpgr knockout mice",
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.",
keywords = "retinitis pigmentosa, RPGR, microglia activation, tauroursodeoxycholic acid, neuroprotection",
author = "Xun Zhang and Uma Shahani and James Reilly and Xinhua Shu",
note = "Acceptance in SAN",
year = "2019",
month = "3",
day = "28",
doi = "10.1002/jcp.28519",
language = "English",
journal = "Journal of Cellular Physiology",
issn = "0021-9541",
publisher = "John Wiley & Sons",

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TY - JOUR

T1 - Disease mechanisms and neuroprotection by tauroursodeoxycholic acid in Rpgr knockout mice

AU - Zhang, Xun

AU - Shahani, Uma

AU - Reilly, James

AU - Shu, Xinhua

N1 - Acceptance in SAN

PY - 2019/3/28

Y1 - 2019/3/28

N2 - 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.

AB - 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.

KW - retinitis pigmentosa

KW - RPGR

KW - microglia activation

KW - tauroursodeoxycholic acid

KW - neuroprotection

U2 - 10.1002/jcp.28519

DO - 10.1002/jcp.28519

M3 - Article

JO - Journal of Cellular Physiology

JF - Journal of Cellular Physiology

SN - 0021-9541

ER -