Disease mechanisms and neuroprotection by tauroursodeoxycholic acid in Rpgr knockout mice.
Mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene are the predominant cause of retinitis pigmentosa. 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 (OSs) of photoreceptors. This trafficking process is controlled directly by intraflagellar transport complexes and regulated by the RPGR protein complex, although the precise mechanisms have yet to be defined. We used 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.
['Zhang|Xun|X|', 'Shahani|Uma|U|', 'Reilly|James|J|', 'Shu|Xinhua|X|0000-0003-3760-3019']
D000818:Animals D017209:Apoptosis D002923:Cilia D004268:DNA-Binding Proteins D004195:Disease Models, Animal D005136:Eye Proteins D018345:Mice, Knockout D017628:Microglia D000066829:Neuroprotection D020419:Photoreceptor Cells, Vertebrate D012160:Retina D012162:Retinal Degeneration D013655:Taurochenodeoxycholic Acid
neuroprotection tauroursodeoxycholic acid RPGR retinitis pigmentosa microglia activation