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bioRxiv · 10.1101/803510

Deletion of M-opsin prevents \"M cone\" degeneration in a mouse model of Leber congenital amaurosis

Xu, H.·Enemchukwu, N.·Zhong, X.·Zhang, O.·Fu, Y.
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Abstract

Mutations in RPE65 or lecithin-retinol acyltransferase (LRAT) disrupt 11-cis-retinal synthesis and cause Leber congenital amaurosis (LCA). In Lrat-/- mouse model, mislocalized medium (M)-wavelength sensitive opsin was degraded whereas mislocalized short (S)-wavelength sensitive opsin accumulated before the onset of cone degeneration. The mechanism for the foveal medium (M)/long (L)-wavelength-sensitive cone degeneration in LCA is unknown. By crossing Lrat-/- mice with a proteasome reporter mouse line, we showed that M-opsin enriched dorsal cones in Lrat-/- mice exhibit proteasome stress due to the degradation of large amounts of M-opsin. Deletion of M-opsin relieves the proteasome stress and completely prevents \"M cone\" degeneration in Lrat-/-Opn1sw-/- mice (a pure \"M cone\" LCA model, Opn1sw-/- encoding S-opsin) for at least 12 months. Our results suggest that M-opsin degradation associated proteasome stress plays a major role in \"M cone\" degeneration in Lrat-/- model. This finding may represent a general mechanism for \"M cone\" degeneration for multiple forms of cone degeneration due to M-opsin mislocalization and degradation. Our results have important implications for the current gene therapy strategy for LCA that emphasizes the need for a combinatorial therapy to both improve vision and slow photoreceptor degeneration.

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Xu, H., Enemchukwu, N., Zhong, X., Zhang, O., Fu, Y.. 2019-10-16. Deletion of M-opsin prevents \"M cone\" degeneration in a mouse model of Leber congenital amaurosis. https://doi.org/10.1101/803510

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