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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 16 week old GHL+ and GHL+/Chop−/− mice.(A) Average scotopic ERG a- and b-wave waveforms from C57BL/6 (blue traces), Chop−/− (orange traces) GHL+ (black traces) and GHL+/Chop−/− (red traces) mice in response to 1 ms flashes of increasing intensity, from bottom to top, (n = 8–13). (B) Intensity-response functions of a- and b-waves. Error bars ± SD. Scale bar: x = 50 ms, y = 200 µV. Arrows represent the onset of light stimulus.
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pone-0083871-g004: ERG responses in 16 week old GHL+ and GHL+/Chop−/− mice.(A) Average scotopic ERG a- and b-wave waveforms from C57BL/6 (blue traces), Chop−/− (orange traces) GHL+ (black traces) and GHL+/Chop−/− (red traces) mice in response to 1 ms flashes of increasing intensity, from bottom to top, (n = 8–13). (B) Intensity-response functions of a- and b-waves. Error bars ± SD. Scale bar: x = 50 ms, y = 200 µV. Arrows represent the onset of light stimulus.

Mentions: At 16 weeks, the approximate midpoint in retinal degeneration in GHL+ mice [51], the maximum a-wave amplitude at saturating light intensity decreased by 52% compared to 4 week old GHL+ mice (Fig. 4). The a-wave amplitude was 22% of C57BL/6 and Chop−/− mice. In some animals the a-wave could not be detected at intensities <+1.74 log cds/m2. The a-wave It decreased by ∼20 fold compared to control mice (p<0.01). At the saturating light intensity, there was a ∼44% decline in the b-wave amplitude of GHL+ mice compared to age matched control animals (p<0.001). The b-wave It was significantly different compared to C57BL/6 mice (p = 0.041) (Table 2).


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 16 week old GHL+ and GHL+/Chop−/− mice.(A) Average scotopic ERG a- and b-wave waveforms from C57BL/6 (blue traces), Chop−/− (orange traces) GHL+ (black traces) and GHL+/Chop−/− (red traces) mice in response to 1 ms flashes of increasing intensity, from bottom to top, (n = 8–13). (B) Intensity-response functions of a- and b-waves. Error bars ± SD. Scale bar: x = 50 ms, y = 200 µV. Arrows represent the onset of light stimulus.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0083871-g004: ERG responses in 16 week old GHL+ and GHL+/Chop−/− mice.(A) Average scotopic ERG a- and b-wave waveforms from C57BL/6 (blue traces), Chop−/− (orange traces) GHL+ (black traces) and GHL+/Chop−/− (red traces) mice in response to 1 ms flashes of increasing intensity, from bottom to top, (n = 8–13). (B) Intensity-response functions of a- and b-waves. Error bars ± SD. Scale bar: x = 50 ms, y = 200 µV. Arrows represent the onset of light stimulus.
Mentions: At 16 weeks, the approximate midpoint in retinal degeneration in GHL+ mice [51], the maximum a-wave amplitude at saturating light intensity decreased by 52% compared to 4 week old GHL+ mice (Fig. 4). The a-wave amplitude was 22% of C57BL/6 and Chop−/− mice. In some animals the a-wave could not be detected at intensities <+1.74 log cds/m2. The a-wave It decreased by ∼20 fold compared to control mice (p<0.01). At the saturating light intensity, there was a ∼44% decline in the b-wave amplitude of GHL+ mice compared to age matched control animals (p<0.001). The b-wave It was significantly different compared to C57BL/6 mice (p = 0.041) (Table 2).

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