Abstract
Disrupted clearance of all-trans-retinal (atRAL), a component of the visual (retinoid) cycle in the retina, may cause photoreceptor atrophy in autosomal recessive Stargardt disease (STGD1) and dry age-related macular degeneration (AMD). However, the mechanisms underlying atRAL-induced photoreceptor loss remain elusive. Here, we report that atRAL activates c-Jun N-terminal kinase (JNK) signaling at least partially through reactive oxygen species production, which promoted mitochondria-mediated caspase- and DNA damage-dependent apoptosis in photoreceptor cells. Damage to mitochondria in atRAL-exposed photoreceptor cells resulted from JNK activation, leading to decreased expression of Bcl2 apoptosis regulator (Bcl2), increased Bcl2 antagonist/killer (Bak) levels, and cytochrome c (Cyt c) release into the cytosol. Cytosolic Cyt c specifically provoked caspase-9 and caspase-3 activation and thereby initiated apoptosis. Phosphorylation of JNK in atRAL-loaded photoreceptor cells induced the appearance of γH2AX, a sensitive marker for DNA damage, and was also associated with apoptosis onset. Suppression of JNK signaling protected photoreceptor cells against atRAL-induced apoptosis. Moreover, photoreceptor cells lacking Jnk1 and Jnk2 genes were more resistant to atRAL-associated cytotoxicity. The Abca4-/-Rdh8-/- mouse model displays defects in atRAL clearance that are characteristic of STGD1 and dry AMD. We found that JNK signaling was activated in the neural retina of light-exposed Abca4-/-Rdh8-/- mice. Of note, intraperitoneal administration of JNK-IN-8, which inhibits JNK signaling, effectively ameliorated photoreceptor degeneration and apoptosis in light-exposed Abca4-/-Rdh8-/- mice. We propose that pharmacological inhibition of JNK signaling may represent a therapeutic strategy for preventing photoreceptor loss in retinopathies arising from atRAL overload.
Highlights
Clearance of all-trans retinal released from photoactivated rhodopsin is very important for sustaining vision[1,2]
We propose that pharmacological inhibition of Jun N-terminal kinases (JNKs) signaling may represent a therapeutic strategy for preventing photoreceptor loss in retinopathies arising from atRAL overload
Imaging of mitochondrial membrane potential (∆Ψm) using rhodamine-123 showed that the treatment of 661W photoreceptor cells with 5 μM atRAL for 6 h significantly reduced the levels of ΔΨm (Fig. 1D)
Summary
Clearance of all-trans retinal (atRAL) released from photoactivated rhodopsin is very important for sustaining vision[1,2]. Immunoblot analysis demonstrated that JNK-IN-8 at a concentration of 1 μM clearly decreased protein levels of p-c-Jun and cleaved caspase-3 in lysates of atRAL-loaded 661W photoreceptor cells (Fig. 2E). Immunoblot analysis demonstrated that treatment with 1 μM JNK-IN-8 significantly reduced protein levels of γH2AX in atRAL-loaded 661W photoreceptor cells (Fig. 3D).
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