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Ablation of the proapoptotic genes CHOP or Ask1 does not prevent or delay loss of visual function in a P23H transgenic mouse model of retinitis pigmentosa.

Adekeye A, Haeri M, Solessio E, Knox BE - PLoS ONE (2014)

Bottom Line: Histologically, ablation of Chop and Ask1 did not rescue photoreceptor loss in young animals.Our results show that in the presence of the Rho(P23H) transgene, the rate of decline in retinal sensitivity is similar in Chop or Ask1 ablated and wild-type retinas, suggesting that these proteins do not play a major role during the acute phase of photoreceptor loss in GHL(+) mice.Instead they may be involved in regulating secondary pathological responses such as inflammation that are upregulated during later stages of disease progression.

View Article: PubMed Central - PubMed

Affiliation: Departments of Neuroscience & Physiology, Biochemistry & Molecular Biology and Ophthalmology, Center for Vision Research, SUNY Upstate Medical University, Syracuse, New York, United States of America.

ABSTRACT
The P23H mutation in rhodopsin (Rho(P23H)) is a prevalent cause of autosomal dominant retinitis pigmentosa. We examined the role of the ER stress proteins, Chop and Ask1, in regulating the death of rod photoreceptors in a mouse line harboring the Rho(P23H) rhodopsin transgene (GHL(+)). We used knockout mice models to determine whether Chop and Ask1 regulate rod survival or retinal degeneration. Electrophysiological recordings showed similar retinal responses and sensitivities for GHL(+), GHL(+)/Chop(-/-) and GHL(+)/Ask1(-/-) animals between 4-28 weeks, by which time all three mouse lines exhibited severe loss of retinal function. Histologically, ablation of Chop and Ask1 did not rescue photoreceptor loss in young animals. However, in older mice, a regional protective effect was observed in the central retina of GHL(+)/Chop(-/-) and GHL(+)/Ask1(-/-), a region that was severely degenerated in GHL(+) mice. Our results show that in the presence of the Rho(P23H) transgene, the rate of decline in retinal sensitivity is similar in Chop or Ask1 ablated and wild-type retinas, suggesting that these proteins do not play a major role during the acute phase of photoreceptor loss in GHL(+) mice. Instead they may be involved in regulating secondary pathological responses such as inflammation that are upregulated during later stages of disease progression.

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Age related changes in retinal function and sensitivity of GHL+ and GHL+/Chop−/− mice.(A) b/a wave ratio in C57BL/6, Chop−/−, GHL+, and GHL+/Chop−/− mice. (B and C) Age related changes in a- and b-wave threshold intensities in C57BL/6, Chop−/−, GHL+, and GHL+/Chop−/− mice (a- wave It = 50 µV, b- wave It = 75 µV). Error bars: ± SD.
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pone-0083871-g007: Age related changes in retinal function and sensitivity of GHL+ and GHL+/Chop−/− mice.(A) b/a wave ratio in C57BL/6, Chop−/−, GHL+, and GHL+/Chop−/− mice. (B and C) Age related changes in a- and b-wave threshold intensities in C57BL/6, Chop−/−, GHL+, and GHL+/Chop−/− mice (a- wave It = 50 µV, b- wave It = 75 µV). Error bars: ± SD.

Mentions: Since the b-wave was higher in GHL+/Chop−/− compared to GHL+ mice, we assessed the signal transmission from photoreceptor cells to second order cells by determining the b/a wave ratio [52]. We determined the b/a ratio by normalizing maximal b-wave amplitudes to maximal a-wave amplitudes and plotted the values as a function of age (Fig. 7A). The b/a ratio is constant in healthy retinas, therefore, deviations from normal b/a ratio represent pathological/degenerative changes in the retina [52]. The b/a ratio was similar between C57BL/6 and Chop−/− mice (Fig. 7A). In GHL+ mice, the b/a ratio was abnormally high at all ages compared to control mice, which is consistent with ongoing degeneration. Similarly, in GHL+/Chop−/− mice, the b/a ratio was higher than C57BL/6 and Chop−/− animals. At all ages, b/a ratio was comparable between GHL+/Chop−/− and GHL+ mice (p>0.05), suggesting that there are no significant differences in signal transmission from photoreceptors to second order cells in GHL+/Chop−/− and GHL+ mice.


Ablation of the proapoptotic genes CHOP or Ask1 does not prevent or delay loss of visual function in a P23H transgenic mouse model of retinitis pigmentosa.

Adekeye A, Haeri M, Solessio E, Knox BE - PLoS ONE (2014)

Age related changes in retinal function and sensitivity of GHL+ and GHL+/Chop−/− mice.(A) b/a wave ratio in C57BL/6, Chop−/−, GHL+, and GHL+/Chop−/− mice. (B and C) Age related changes in a- and b-wave threshold intensities in C57BL/6, Chop−/−, GHL+, and GHL+/Chop−/− mice (a- wave It = 50 µV, b- wave It = 75 µV). Error bars: ± SD.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3921110&req=5

pone-0083871-g007: Age related changes in retinal function and sensitivity of GHL+ and GHL+/Chop−/− mice.(A) b/a wave ratio in C57BL/6, Chop−/−, GHL+, and GHL+/Chop−/− mice. (B and C) Age related changes in a- and b-wave threshold intensities in C57BL/6, Chop−/−, GHL+, and GHL+/Chop−/− mice (a- wave It = 50 µV, b- wave It = 75 µV). Error bars: ± SD.
Mentions: Since the b-wave was higher in GHL+/Chop−/− compared to GHL+ mice, we assessed the signal transmission from photoreceptor cells to second order cells by determining the b/a wave ratio [52]. We determined the b/a ratio by normalizing maximal b-wave amplitudes to maximal a-wave amplitudes and plotted the values as a function of age (Fig. 7A). The b/a ratio is constant in healthy retinas, therefore, deviations from normal b/a ratio represent pathological/degenerative changes in the retina [52]. The b/a ratio was similar between C57BL/6 and Chop−/− mice (Fig. 7A). In GHL+ mice, the b/a ratio was abnormally high at all ages compared to control mice, which is consistent with ongoing degeneration. Similarly, in GHL+/Chop−/− mice, the b/a ratio was higher than C57BL/6 and Chop−/− animals. At all ages, b/a ratio was comparable between GHL+/Chop−/− and GHL+ mice (p>0.05), suggesting that there are no significant differences in signal transmission from photoreceptors to second order cells in GHL+/Chop−/− and GHL+ mice.

Bottom Line: Histologically, ablation of Chop and Ask1 did not rescue photoreceptor loss in young animals.Our results show that in the presence of the Rho(P23H) transgene, the rate of decline in retinal sensitivity is similar in Chop or Ask1 ablated and wild-type retinas, suggesting that these proteins do not play a major role during the acute phase of photoreceptor loss in GHL(+) mice.Instead they may be involved in regulating secondary pathological responses such as inflammation that are upregulated during later stages of disease progression.

View Article: PubMed Central - PubMed

Affiliation: Departments of Neuroscience & Physiology, Biochemistry & Molecular Biology and Ophthalmology, Center for Vision Research, SUNY Upstate Medical University, Syracuse, New York, United States of America.

ABSTRACT
The P23H mutation in rhodopsin (Rho(P23H)) is a prevalent cause of autosomal dominant retinitis pigmentosa. We examined the role of the ER stress proteins, Chop and Ask1, in regulating the death of rod photoreceptors in a mouse line harboring the Rho(P23H) rhodopsin transgene (GHL(+)). We used knockout mice models to determine whether Chop and Ask1 regulate rod survival or retinal degeneration. Electrophysiological recordings showed similar retinal responses and sensitivities for GHL(+), GHL(+)/Chop(-/-) and GHL(+)/Ask1(-/-) animals between 4-28 weeks, by which time all three mouse lines exhibited severe loss of retinal function. Histologically, ablation of Chop and Ask1 did not rescue photoreceptor loss in young animals. However, in older mice, a regional protective effect was observed in the central retina of GHL(+)/Chop(-/-) and GHL(+)/Ask1(-/-), a region that was severely degenerated in GHL(+) mice. Our results show that in the presence of the Rho(P23H) transgene, the rate of decline in retinal sensitivity is similar in Chop or Ask1 ablated and wild-type retinas, suggesting that these proteins do not play a major role during the acute phase of photoreceptor loss in GHL(+) mice. Instead they may be involved in regulating secondary pathological responses such as inflammation that are upregulated during later stages of disease progression.

Show MeSH
Related in: MedlinePlus