The role of transducin signaling in retinal degenerative disease
Brill, Elliott R.
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Retinitis pigmentosa (RP) is a collection of inherited retinal degenerations that afflicts 50,000- 100,000 people in the United States. The hallmark pathology of RP is apoptosis of photoreceptor cells. Currently there is no treatment for this disease. The equivalent light hypothesis states that some RP mutations cause retinal degeneration by mimicking a continuous phototransduction signal. We tested this hypothesis in transducin knockout (TKO-/-) mice, deficient for the a - subunit of transducin, the heterotrimeric G-protein which mediates light signaling in photoreceptors. Methods: We used light microscopy to compare the retinal morphology of TKO-/- and wild-type (TKO+/+) mice: 1) exposed to continuous bright light, or 2) crossed with mice carrying three different rhodopsin mutations leading to retinal degeneration: A) Proline347Serine (P347S), B) Valine20Giycine, Proline23Histidine, Proline27Leucine (VPP), and C) Lysine296Giutamic acid (K296E). Results: We predicted two types of photoreceptor cell apoptosis: 1) signal-dependent mutants in which degeneration was blocked in the absence of transducin, and 2) signal-independent mutants, not affected by the presence or absence of transducin signaling. To our surprise,we found three classes of retinal degeneration: 1) the VPP triple mutant caused photoreceptor apoptosis, at the same rate, regardless of the presence or absence of a-transducin, 2) the P347S and K296E opsin mutants caused an accelerated rate of degeneration on the TKO -/- background as compared to on the TKO+/+ background, and 3) the damaging effects of continuous light were retarded on the null transducin background. These data support the equivalent light hypothesis as a mechanism for some, but not all forms of retinal degeneration. Thus, the cellular signal that triggers photoreceptor apoptosis can occur either upstream or downstream of transducin signaling. Classifying different types of mutations that lead to photoreceptor cell death will be important for determining effective therapies for different classes of human retinal degeneration.
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