Researchers here uncover a protective mechanism that helps retinal cells resist stresses. It is observed to slow the development of conditions such as glaucoma, but also to slow the more general age-related declines in retinal function. Whether this is a suitable basis for the production of useful therapies remains to be seen. Slowing the progression of age-related loss of function is a poor substitute for repair and rejuvenation. So if funding is to be directed to the production of therapies, one would hope that priority is given to methods that repair damage rather than methods that slow the consequences of damage.
The retina, as the fundamental structural tissue to encode and transmit visual signals into the brain, is organized by diverse cell types mediating the signal transduction cooperatively. The degenerations in the aging retina are associated with such diseases as the progressive degeneration of photoreceptors in aging-related macular degeneration and retinal ganglion cells (RGCs) degeneration in glaucoma. In addition, disease-free vision decline is also relevant to structural and physiological changes in the retina, including RGC dendrite shrinking, retinal pigment epithelium degeneration, and photoreceptor dysfunction.
Previously we discovered that the m6A reader YTHDF2 negatively regulates dendrite development and injury of RGCs. The expansion of RGC dendrite arbors and more synapses in the inner plexiform layer after conditional knockout (cKO) of Ythdf2 in the retina modestly improve the visual acuity of mice in an optomotor assay. In the glaucoma models, the m6A writers METTL3 and WTAP, and its reader YTHDF2, are upregulated, and the loss-of-function of YTHDF2 has a neuroprotective role. However, it remains unknown whether m6A modification and its reader YTHDF2 regulate the degeneration of RGCs in the aged retinas.
Here, we show that conditional ablation of Ythdf2 protects the retina from RGC dendrite shrinking and vision loss in aged mice. Additionally, we identify Hspa12a and Islr2 as the potential YTHDF2 target mRNAs mediating these effects. Together, our results indicate that the m6A reader YTHDF2 regulates retinal degeneration caused by aging, which might provide important therapeutic potential for developing new treatment approaches against aging-related vision loss.
Link: https://doi.org/10.1111/acel.70107
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