Abstract
Damage and loss of the postmitotic photoreceptors is a leading cause of blindness in many diseases of the eye. Although the mechanisms of photoreceptor death have been extensively studied, few studies have addressed mechanisms that help sustain these non-replicating neurons for the life of an organism. Autophagy is an intracellular pathway where cytoplasmic constituents are delivered to the lysosomal pathway for degradation. It is not only a major pathway activated in response to cellular stress, but is also important for cytoplasmic turnover and to supply the structural and energy needs of cells. We examined the importance of autophagy in photoreceptors by deleting the essential autophagy gene Atg5 specifically in rods. Loss of autophagy led to progressive degeneration of rod photoreceptors beginning at 8 weeks of age such that by 44 weeks few rods remained. Cone photoreceptor numbers were only slightly diminished following rod degeneration but their function was significantly decreased. Rod cell death was apoptotic but was not dependent on daily light exposure or accelerated by intense light. Although the light-regulated translocation of the phototransduction proteins arrestin and transducin were unaffected in rods lacking autophagy, Atg5-deficient rods accumulated transducin-α as they degenerated suggesting autophagy might regulate the level of this protein. This was confirmed when the light-induced decrease in transducin was abolished in Atg5-deficient rods and the inhibition of autophagy in retinal explants cultures prevented its degradation. These results demonstrate that basal autophagy is essential to the long-term health of rod photoreceptors and a critical process for maintaining optimal levels of the phototransduction protein transducin-α. As the lack of autophagy is associated with retinal degeneration and altered phototransduction protein degradation in the absence of harmful gene products, this process may be a viable therapeutic target where rod cell loss is the primary pathologic event.
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Abbreviations
- L/D:
-
light/dark
- Atg5:
-
autophagy-related gene 5
- Tα:
-
rod transducin alpha subunit
- Gnat1:
-
guanine nucleotide binding protein alpha transducin 1
- Arr:
-
arrestin
- CMA:
-
chaperone-mediated autophagy
- LC3B:
-
Microtubule-associated protein 1 light chain 3 beta
- RPE:
-
retinal pigment epithelium
- ONL:
-
outer nuclear layer
- OS:
-
outer segments
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Acknowledgements
We would like to thank Frank Schottler for his assistance with transmission electron microscopy. This work was supported by a National Institutes of Health Grants EY015570 (TAF), EY019287 (RSA), EY02687 (Department of Ophthalmology and Visual Science Core Grant), a Department of Ophthalmology and Visual Science unrestricted grant from Research to Prevent Blindness, New York, NY, Research to Prevent Blindness Inc. Career Development Award and Physician Scientist Award (RSA), Carl Marshall Reeves and Mildred Almen Reeves Foundation Inc. Award (RSA and TAF) and The BrightFocus Foundation, Clarksburg, MD (TAF).
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Zhou, Z., Doggett, T., Sene, A. et al. Autophagy supports survival and phototransduction protein levels in rod photoreceptors. Cell Death Differ 22, 488–498 (2015). https://doi.org/10.1038/cdd.2014.229
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DOI: https://doi.org/10.1038/cdd.2014.229
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