SEARCHOTHERophthalmology, retina

other·ophthalmology, retina, preclinical research, biomedical research·PMC10250166

HSP90α is needed for the survival of rod photoreceptors and regulates the expression of rod PDE6 subunits

The Journal of Biological Chemistry · 7 authors, 3 centres

AI SUMMARY

FIDELITY 100%

POPULATIONWild-type and HSP90α knockout mice

INTERVENTIONGenetic knockout of HSP90α

COMPARISONLittermate wild-type controls

This summary was generated by AI from a single paper. It has not been reviewed by a clinician and is not clinical advice. Verify against the source before acting on it.

AGENT 01 · STRUCTURED SUMMARY

TRACE TO SOURCE

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TL;DR

Using a novel HSP90α knockout mouse model, this study found that the HSP90α chaperone is essential for maintaining rod photoreceptor function and survival, leading to progressive degeneration of rods upon its loss, while cone photoreceptors were unaffected.

Full summary

938 CHARS

This preclinical study used a novel HSP90α-specific knockout mouse to investigate the chaperone's role in the retina. The central finding is that HSP90α is essential for rod photoreceptor survival but not cone photoreceptors. Rod dysfunction was first detected at 2 months via electroretinography (ERG), accompanied by structural abnormalities like vacuoles and outer segment defects. This progressed to complete rod degeneration by 6 months. Cone function loss was a secondary 'bystander effect.' Proteomic analysis revealed HSP90α regulates less than 1% of the retinal proteome, but critically, it maintains the levels of rod-specific phosphodiesterase 6 (PDE6) subunits and its cochaperone AIPL1. Cone PDE6 levels were unaffected, possibly due to compensation by HSP90β. The implications are that HSP90α-specific functions in rod cells may help explain side effects like night blindness seen with pan-HSP90 inhibitors in cancer trials.

PICO

PPOPULATION

Wild-type and HSP90α knockout mice

IINTERVENTION

Genetic knockout of HSP90α

OOUTCOME

Rod and cone photoreceptor function (scotopic and photopic ERG), photoreceptor degeneration, and protein levels (PDE6, AIPL1)

STUDY TYPE

other

SPECIALTY

ophthalmology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

100% · A

ORIGINAL PAPER

PMC10250166

HSP90α is needed for the survival of rod photoreceptors and regulates the expression of rod PDE6 subunits

The Journal of Biological Chemistry

READ THE FULL PAPER

ABSTRACT

Heat shock protein 90 (HSP90) is an abundant molecular chaperone that regulates the stability of a small set of proteins essential in various cellular pathways. Cytosolic HSP90 has two closely related paralogs: HSP90α and HSP90β. Due to the structural and sequence similarities of cytosolic HSP90 paralogs, identifying the unique functions and substrates in the cell remains challenging. In this article, we assessed the role of HSP90α in the retina using a novel HSP90α murine knockout model. Our findings show that HSP90α is essential for rod photoreceptor function but was dispensable in cone photoreceptors. In the absence of HSP90α, photoreceptors developed normally. We observed rod dysfunction in HSP90α knockout at 2 months with the accumulation of vacuolar structures, apoptotic nuclei, and abnormalities in the outer segments. The decline in rod function was accompanied by progressive degeneration of rod photoreceptors that was complete at 6 months. The deterioration in cone function and health was a “bystander effect” that followed the degeneration of rods. Tandem mass tag proteomics showed that HSP90α regulates the expression levels of <1% of the retinal proteome. More importantly, HSP90α was vital in maintaining rod PDE6 and AIPL1 cochaperone levels in rod photoreceptor cells. Interestingly, cone PDE6 levels were unaffected. The robust expression of HSP90β paralog in cones likely compensates for the loss of HSP90α. Overall, our study demonstrated the critical need for HSP90α chaperone in the maintenance of rod photoreceptors and showed potential substrates regulated by HSP90α in the retina.

CITATION EXPORT

Daniella Munezero, Hunter Aliff, Ezequiel Salido et al.. HSP90α is needed for the survival of rod photoreceptors and regulates the expression of rod PDE6 subunits. The Journal of Biological Chemistry. (2023). https://doi.org/10.1016/j.jbc.2023.104809

AUTHORS

7 · 3 CENTRES

Daniella Munezero, Hunter Aliff, Ezequiel Salido, Thamaraiselvi Saravanan, Urikhan Sanzhaeva, Tongju Guan, Visvanathan Ramamurthy

1Department of Pharmaceutical and Pharmacological Sciences, West Virginia University, Morgantown, West Virginia, USA
2Ophthalmology and Visual Sciences, West Virginia University, Morgantown, West Virginia, USA
3Biochemistry and Molecular Medicine, West Virginia University, Morgantown, West Virginia, USA