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Endoplasmic Reticulum Stress in Mouse Models of Neurodegeneration


The endoplasmic reticulum is an organelle that responsible for the folding and processing of newly synthesized proteins. When unfolded or misfolded proteins accumulate in the ER and disrupt proper function this leads to a phenomenon known as ER stress. When this occurs, the UPR is activated in order to reduce ER load and restore the ER to its normal function. ATF6, IRE1, and PERK are the three pathways of the UPR. Here, I studied ER stress and the UPR in relation to retinitis pigmentosa, achromatopsia, and retinal degeneration in a tauopathy mouse model. I found that P23H rhodopsin, which is one of the most common mutated proteins involved with the development of retinitis pigmentosa, is highly ubiquitinated by several E3 ubiquitin ligases in order to be targeted for degradation. In addition, knocking out ATF6 seems to increase activation of IRE1 and preserve rhodopsin levels in the case of Rho+/P23H mice. In the achromatopsia study, Class 2 ATF6 mutants experience constitutive transcriptional activation and Class 3 ATF6 mutants are transcriptionally inactive, which can help explain causation of disease development. In the preliminary studies of the PS19 mouse model, I found that there is retinal degeneration and loss of visual function occurring in these mice compared to their wildtype littermates.

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