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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 responses in GHL+ and GHL+/Ask1−/− mice.Intensity-response functions of a- and b-waves in (A) 4, (B) 16, and (C) 28 week old C57BL/6 (blue), Ask1−/− (green) GHL+ (black) and GHL+/Ask1−/− (purple) mice (n = 7–14). Error bars: ± SD.
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pone-0083871-g008: ERG responses in GHL+ and GHL+/Ask1−/− mice.Intensity-response functions of a- and b-waves in (A) 4, (B) 16, and (C) 28 week old C57BL/6 (blue), Ask1−/− (green) GHL+ (black) and GHL+/Ask1−/− (purple) mice (n = 7–14). Error bars: ± SD.

Mentions: At the saturating light intensity, there was a ∼55% decreased in the a-wave amplitude of 4 week old GHL+/Ask1−/− mice compared to C57BL/6 and Ask1−/− mice (p<0.001). The maximum a-wave amplitude was 17% higher than the maximum a-wave of GHL+ mice (Fig. 8A), however the difference was not statistically significant (p = 0.294, n = 7–9). Similarly, the a-wave It (Table 1) was significantly different from C57BL/6 and Ask1−/− mice (p<0.001), but not significantly different from GHL+ mice (p = 0.163).


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 responses in GHL+ and GHL+/Ask1−/− mice.Intensity-response functions of a- and b-waves in (A) 4, (B) 16, and (C) 28 week old C57BL/6 (blue), Ask1−/− (green) GHL+ (black) and GHL+/Ask1−/− (purple) mice (n = 7–14). Error bars: ± SD.
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Related In: Results  -  Collection

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

pone-0083871-g008: ERG responses in GHL+ and GHL+/Ask1−/− mice.Intensity-response functions of a- and b-waves in (A) 4, (B) 16, and (C) 28 week old C57BL/6 (blue), Ask1−/− (green) GHL+ (black) and GHL+/Ask1−/− (purple) mice (n = 7–14). Error bars: ± SD.
Mentions: At the saturating light intensity, there was a ∼55% decreased in the a-wave amplitude of 4 week old GHL+/Ask1−/− mice compared to C57BL/6 and Ask1−/− mice (p<0.001). The maximum a-wave amplitude was 17% higher than the maximum a-wave of GHL+ mice (Fig. 8A), however the difference was not statistically significant (p = 0.294, n = 7–9). Similarly, the a-wave It (Table 1) was significantly different from C57BL/6 and Ask1−/− mice (p<0.001), but not significantly different from GHL+ mice (p = 0.163).

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