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

Area of Science:

• Molecular Biology
• Neuroscience
• Genetics

Background:

• Heat Shock Protein 90 (HSP90) is a crucial molecular chaperone with two cytosolic paralogs, HSP90α and HSP90β.
• HSP90α deficiency in mice leads to progressive rod photoreceptor degeneration, despite normal retinal development and HSP90β presence.

Purpose of the Study:

• To determine if HSP90β can functionally replace HSP90α in mouse photoreceptors.
• To investigate the specific role of HSP90α in maintaining retinal function.

Main Methods:

• Adeno-associated virus (AAV) vectors were engineered to express HA-tagged HSP90α or HSP90β.
• Subretinal delivery of AAV vectors was performed in Hsp90α knockout mice.
• Rod function was assessed using electroretinography (ERG), and photoreceptor degeneration was monitored.

Main Results:

• AAV-mediated expression of HSP90α successfully restored rod function and prevented degeneration in Hsp90α knockout mice.
• Expression of HSP90β via AAV failed to rescue rod function or prevent degeneration, despite similar expression levels.
• Overexpressing either HSP90α or HSP90β in wild-type mice did not cause adverse retinal effects.

Conclusions:

• HSP90α has a non-redundant, essential function in mouse rod photoreceptors.
• HSP90β cannot functionally substitute for HSP90α in the retina, highlighting paralog-specific requirements.