Stable rhodopsin/arrestin complex leads to retinal degeneration in a transgenic mouse model of autosomal dominant retinitis pigmentosa.
Over 100 rhodopsin mutation alleles have been associated with autosomal dominant retinitis pigmentosa (ADRP). These mutations appear to cause photoreceptor cell death through diverse molecular mechanisms. We show that K296E, a rhodopsin mutation associated with ADRP, forms a stable complex with arrestin that is toxic to mouse rod photoreceptors. This cell death pathway appears to be conserved from flies to mammals. A genetics approach to eliminate arrestin unmasked the constitutive activity of K296E and caused photoreceptor cell death through a transducin-dependent mechanism that is similar to light damage. Expressing K296E in the arrestin/transducin double knock-out background prevented transducin signaling and led to substantially improved retinal morphology but did not fully prevent cell death caused by K296E. The adverse effect of K296E in the arrestin/transducin knock-out background can be mimicked by constant exposure to low light. Furthermore, we found that arrestin binding causes K296E to mislocalize to the wrong cellular compartment. Accumulation of stable rhodopsin/arrestin complex in the inner segment may be an important mechanism for triggering the cell death pathway in the mammalian photoreceptor cell.
Chen
Jiayan
J
Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California 90033, USA.
Shi
Guang
G
Concepcion
Francis A
FA
Xie
Guifu
G
Oprian
Daniel
D
Chen
Jeannie
J
D000818:Animals; D019393:Arrestin / Q000235:genetics / Q000378:metabolism*; D002451:Cell Compartmentation / Q000235:genetics; D016923:Cell Death / Q000235:genetics; D025063:Chromosome Disorders / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D005799:Genes, Dominant / Q000235:genetics; D006801:Humans; D008027:Light / Q000009:adverse effects; D046911:Macromolecular Substances / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D012243:Rhodopsin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D015293:Transducin / Q000235:genetics
D019393:Arrestin; D046911:Macromolecular Substances; D012243:Rhodopsin; D015293:Transducin