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Mechanisms of neurodegeneration in a preclinical autosomal dominant retinitis pigmentosa knock-in model with a RhoD190N mutation.

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.

SUBMITTER: Sancho-Pelluz J 

PROVIDER: S-EPMC7144803 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Mechanisms of neurodegeneration in a preclinical autosomal dominant retinitis pigmentosa knock-in model with a Rho<sup>D190N</sup> mutation.

Sancho-Pelluz Javier J   Cui Xuan X   Lee Winston W   Tsai Yi-Ting YT   Wu Wen-Hsuan WH   Justus Sally S   Washington Ilyas I   Hsu Chun-Wei CW   Park Karen Sophia KS   Koch Susanne S   Velez Gabriel G   Bassuk Alexander G AG   Mahajan Vinit B VB   Lin Chyuan-Sheng CS   Tsang Stephen H SH  

Cellular and molecular life sciences : CMLS 20190411 18

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 D1  ...[more]

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