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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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ERG changes as a function of age in GHL+ and GHL+/Chop−/− mice.Maximal a- and b-wave amplitudes as a function of age in C57BL/6 (blue trace), Chop−/− (orange trace) GHL+ (black trace) and GHL+/Chop−/− (red trace) mice. Colored lines are polynomial fits.
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pone-0083871-g006: ERG changes as a function of age in GHL+ and GHL+/Chop−/− mice.Maximal a- and b-wave amplitudes as a function of age in C57BL/6 (blue trace), Chop−/− (orange trace) GHL+ (black trace) and GHL+/Chop−/− (red trace) mice. Colored lines are polynomial fits.

Mentions: We determined the effect of Chop on the rate of degeneration during the major phase of rod loss, between 4–28 weeks. In control C57BL6 and Chop−/− mice there were ∼26% (p = 0.001) and ∼23% (p = 0.008) losses in maximum a-wave amplitudes, respectively, which is similar to what has been reported previously [50] (Fig. 6A). Linear regression for a-wave amplitudes between 4 and 28 weeks showed a downward trend with age in C57BL/6 mice (−4.15±0.51 µV/week) and Chop−/− mice (−3.8±0.73 µV/week) (Fig. 6A). Likewise, there were 24% (p = 0.004) and ∼26% (p<0.001) losses in maximum b-wave amplitudes respectively, in C57BL6 and Chop−/− mice (Fig. 6B, Fig. S1). Linear regression of b-wave amplitudes trended downwards in C57BL/6 mice (−12.7±2.3 µV/week) and Chop−/− mice (−13.3±2.5 µV/week) (Fig. 6B). Therefore the rate of loss of retinal responses was similar in C57BL/6 and Chop−/− 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)

ERG changes as a function of age in GHL+ and GHL+/Chop−/− mice.Maximal a- and b-wave amplitudes as a function of age in C57BL/6 (blue trace), Chop−/− (orange trace) GHL+ (black trace) and GHL+/Chop−/− (red trace) mice. Colored lines are polynomial fits.
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Related In: Results  -  Collection

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Show All Figures
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pone-0083871-g006: ERG changes as a function of age in GHL+ and GHL+/Chop−/− mice.Maximal a- and b-wave amplitudes as a function of age in C57BL/6 (blue trace), Chop−/− (orange trace) GHL+ (black trace) and GHL+/Chop−/− (red trace) mice. Colored lines are polynomial fits.
Mentions: We determined the effect of Chop on the rate of degeneration during the major phase of rod loss, between 4–28 weeks. In control C57BL6 and Chop−/− mice there were ∼26% (p = 0.001) and ∼23% (p = 0.008) losses in maximum a-wave amplitudes, respectively, which is similar to what has been reported previously [50] (Fig. 6A). Linear regression for a-wave amplitudes between 4 and 28 weeks showed a downward trend with age in C57BL/6 mice (−4.15±0.51 µV/week) and Chop−/− mice (−3.8±0.73 µV/week) (Fig. 6A). Likewise, there were 24% (p = 0.004) and ∼26% (p<0.001) losses in maximum b-wave amplitudes respectively, in C57BL6 and Chop−/− mice (Fig. 6B, Fig. S1). Linear regression of b-wave amplitudes trended downwards in C57BL/6 mice (−12.7±2.3 µV/week) and Chop−/− mice (−13.3±2.5 µV/week) (Fig. 6B). Therefore the rate of loss of retinal responses was similar in C57BL/6 and Chop−/− 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