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bioRxiv · 10.1101/2025.06.05.657739

HSP90α is specifically required for rod photoreceptor function and cannot be replaced by HSP90β.

Hoda, J.·Aliff, H.·Deng, W.-T.·Ramamurthy, V.
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Abstract

Heat Shock Protein 90 (HSP90) is a critical molecular chaperone that exists as two cytosolic paralogs, HSP90 and HSP90{beta}, which share high sequence identity but may perform non-redundant functions in vivo. Loss of HSP90 in mice results in progressive rod photoreceptor degeneration despite normal retinal development and expression of HSP90{beta}. To investigate whether HSP90{beta} can substitute for HSP90 in photoreceptors, we generated adeno-associated virus (AAV) vectors expressing HA-tagged HSP90 or HSP90{beta} under the control of a short rhodopsin promoter. In Hsp90 -/- mice, subretinal delivery of AAV-Hsp90aa1 (HSP90) restored rod function and prevented photoreceptor degeneration, as measured by electroretinography (ERG). In contrast, AAV-mediated expression of HSP90{beta} failed to rescue rod function despite comparable expression levels. Overexpression of either paralog in wild-type mice had no adverse effects on retinal function. These findings reveal a paralog-specific and intrinsic requirement for HSP90 in rod photoreceptors, demonstrating that HSP90{beta} cannot compensate for its loss despite structural similarity.

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Hoda, J., Aliff, H., Deng, W.-T., Ramamurthy, V.. 2025-06-05. HSP90α is specifically required for rod photoreceptor function and cannot be replaced by HSP90β.. https://doi.org/10.1101/2025.06.05.657739

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