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- Title
Mechanisms of neurodegeneration in a preclinical autosomal dominant retinitis pigmentosa knock-in model with a Rho<sup>D190N</sup> mutation.
- Authors
Sancho-Pelluz, Javier; Cui, Xuan; Lee, Winston; Tsai, Yi-Ting; Wu, Wen-Hsuan; Justus, Sally; Washington, Ilyas; Hsu, Chun-Wei; Park, Karen Sophia; Koch, Susanne; Velez, Gabriel; Bassuk, Alexander G.; Mahajan, Vinit B.; Lin, Chyuan-Sheng; Tsang, Stephen H.
- Abstract
D190N, a missense mutation in rhodopsin, causes photoreceptor degeneration in patients with autosomal dominant retinitis pigmentosa (adRP). Two competing hypotheses have been developed to explain why D190N rod photoreceptors degenerate: (a) defective rhodopsin trafficking prevents proteins from correctly exiting the endoplasmic reticulum, leading to their accumulation, with deleterious effects or (b) elevated mutant rhodopsin expression and unabated signaling causes excitotoxicity. A knock-in D190N mouse model was engineered to delineate the mechanism of pathogenesis. Wild type (wt) and mutant rhodopsin appeared correctly localized in rod outer segments of D190N heterozygotes. Moreover, the rhodopsin glycosylation state in the mutants appeared similar to that in wt mice. Thus, it seems plausible that the injurious effect of the heterozygous mutation is not related to mistrafficking of the protein, but rather from constitutive rhodopsin activity and a greater propensity for chromophore isomerization even in the absence of light.
- Subjects
PHOTORECEPTORS; RETINITIS pigmentosa; RHODOPSIN; MISSENSE mutation; NEURODEGENERATION; ENDOPLASMIC reticulum
- Publication
Cellular & Molecular Life Sciences, 2019, Vol 76, Issue 18, p3657
- ISSN
1420-682X
- Publication type
Article
- DOI
10.1007/s00018-019-03090-9