Divergent Effects of HSP70 Overexpression in Photoreceptors During Inherited Retinal Degeneration
| Autor: | Atsuhiro Kanda, Elizabeth Fairless, Tiziana Cogliati, Norimoto Gotoh, Ke Jiang, Anand Swaroop, Tiansen Li |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Genetically modified mouse Retinal degeneration Cell Survival Immunoblotting heat shock protein Mice Transgenic Biology Photoreceptor cell Retina 03 medical and health sciences Mice 0302 clinical medicine PDE6B Retinal Rod Photoreceptor Cells Heat shock protein medicine Electroretinography chaperone Animals HSP70 Heat-Shock Proteins proteostasis medicine.diagnostic_test Retinal Degeneration Biochemistry and Molecular Biology photoreceptors medicine.disease Cell biology Mice Inbred C57BL Disease Models Animal 030104 developmental biology medicine.anatomical_structure Proteostasis Gene Expression Regulation Microscopy Fluorescence 030217 neurology & neurosurgery |
| Zdroj: | Investigative Ophthalmology & Visual Science |
| ISSN: | 1552-5783 0146-0404 |
| Popis: | Purpose Disruption of proteostasis is a key event in many neurodegenerative diseases. Heat shock proteins (HSPs) participate in multiple functions associated with intracellular transport and proteostasis. We evaluated the effect of augmented HSP70 expression in mutant photoreceptors of mouse retinal degeneration models to test the hypothesis that failure to sustain HSP70 expression contributes to photoreceptor cell death. Methods We examined HSP70 expression in retinas of wild-type and mutant mice by RNA and protein analysis. A transgenic mouse line, TgCrx-Hspa1a-Flag, was generated to express FLAG-tagged full-length HSP70 protein under control of a 2.3 kb mouse Crx promoter. This line was crossed to three distinct retinal degeneration mouse models. Retinal structure and function were evaluated by histology, immunohistochemistry, and electroretinography. Results In seven different mouse models of retinal degeneration, we detected transient elevation of endogenous HSP70 expression at early stages, followed by a dramatic reduction as cell death ensues, suggesting an initial adaptive response to cellular stress. Augmented expression of HSP70 in RHOT17M mice, in which mutant rhodopsin is misfolded, marginally improved photoreceptor survival, whereas elevated HSP70 led to more severe retinal degeneration in rd10 mutants that produce a partially functional PDE6B. In Rpgrip1-/- mice that display a ciliary defect, higher HSP70 had no impact on photoreceptor survival or function. Conclusions HSP70 overexpression has divergent effects in photoreceptors determined, at least in part, by the nature of the mutant protein each model carries. Additional investigations on HSP pathways and associated chaperone networks in photoreceptors are needed before designing therapeutic strategies targeting proteostasis. |
| Databáze: | OpenAIRE |
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