Caspase-3 inhibitor reduces apototic photoreceptor cell deathduring inherited retinal degeneration in tubby mice

[摘要] Purpose: The tubby mouse, previously suggested as an animalmodel for the human Usher Syndrome type I, was used in an analysis ofpathophysiological processes leading to the inherited retinaldegeneration, also shown in Usher syndrome patients. To evaluatepathogenic mechanisms causing retinal degeneration in tubby mice, weexamined the time course of apoptotic photoreceptor cell death.Apoptotic pathways were determined by the inhibition of specificcaspases in vivo.Methods: Apoptotic cells were identified during retinaldifferentiation and degeneration by the TUNEL-method. Apoptotic eventswere confirmed by DNA-laddering. Intravitreal injection of apoptosisinhibitors was applied to reduce apoptotic photoreceptor cell death intubby mice.Results: During retinal differentiation there is no apparentdifference between tubby and wild type mice in apoptotic events.Between post natal day 16 and 23, apoptosis was detected in the outernuclear layer of tubby mice retinas, but was absent in control mice.The number of TUNEL-labeled photoreceptor cells peaked at post natal day19. After this peak of apoptosis, the number of apoptotic photoreceptorcells gradually decreased. While a caspase-1 inhibitor did not reducethe number of apoptotic cells, a specific caspase-3 inhibitor caused asignificant decrease of apoptotic photoreceptor cells in the tubbymouse retina.Conclusions: Apoptosis is necessary for appropriate differentiationof the retina of tubby and wild type mice. In the fully developedtubby mouse retina, apoptotic photoreceptor cell death leads to retinaldegeneration. Apoptosis in the tubby mouse retina is mediated byspecific activation of members of the caspase-3 family. Caspase-3inhibition drastically reduces photoreceptor cell death in thedegenerating tubby mouse retina and may be a potential tool fortherapeutic strategies of retinal degeneration in human Usher patients.

[学科分类] 生物化学/生物物理