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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 morphology of GHL+ and GHL+/Ask1−/− mice.(A) b/a wave ratio in C57BL/6, Ask1−/−, GHL+, and GHL+/Ask1−/− mice. (B) Representative sections of retinas from 16 week old C57BL/6, Ask1−/−, GHL+ and GHL+/Ask1−/− mice. GHL+ and GHL+/Ask1−/− retinas had shortened OS (arrowheads). (C) Mean number of photoreceptor nuclei per column counted in the ONL. Error bars: ± SD. OPL: outer plexiform layer, ONL: outer nuclear layer, OS: outer segment. Scale bar 50 µm. (D) The variance in the number of photoreceptor nuclei per column counted in different zones of the retina in GHL+ and GHL+/Ask1−/− mice, (right panel). Superior zone: 630 µm from the CMZ, central zone: 630 µm from optic nerve, and inferior zone: midpoint of inferior hemisphere.
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pone-0083871-g010: Age related changes in retinal function and morphology of GHL+ and GHL+/Ask1−/− mice.(A) b/a wave ratio in C57BL/6, Ask1−/−, GHL+, and GHL+/Ask1−/− mice. (B) Representative sections of retinas from 16 week old C57BL/6, Ask1−/−, GHL+ and GHL+/Ask1−/− mice. GHL+ and GHL+/Ask1−/− retinas had shortened OS (arrowheads). (C) Mean number of photoreceptor nuclei per column counted in the ONL. Error bars: ± SD. OPL: outer plexiform layer, ONL: outer nuclear layer, OS: outer segment. Scale bar 50 µm. (D) The variance in the number of photoreceptor nuclei per column counted in different zones of the retina in GHL+ and GHL+/Ask1−/− mice, (right panel). Superior zone: 630 µm from the CMZ, central zone: 630 µm from optic nerve, and inferior zone: midpoint of inferior hemisphere.

Mentions: At 28 weeks, the maximal b-wave amplitude (484±117 µV) declined by 50% (p<0.001) of the 4 weeks value in GHL+/Ask1−/− mice (Fig. 9B). Between 4–28 weeks, the maximum b-wave amplitudes were 14–57% higher (p<0.01) in GHL+/Ask1−/− compared to GHL+ mice. Regression of b-wave amplitudes with age was −22.1±3.11 µV/week in GHL+/Ask1−/− mice (Fig. 9B). The rate of decline in b-wave responses was similar in GHL+ and GHL+/Ask1−/− but faster than C57BL/6, Ask1−/− control mice. However, there were significant differences in maximal b-wave amplitudes in GHL+ and GHL+/Ask1−/− mice compared to control mice. To assess signal transmission through the retina we determined the b/a ratio of GHL+/Ask1−/− mice (Fig. 10A). The b/a ratio was similar between C57BL/6 and Ask1−/− mice (Fig. 10A). In GHL+/Ask1−/− mice, the b/a ratio was higher than control C57BL/6 and Ask1−/− animals, but was comparable to GHL+ mice (p>0.05) (Fig. 10A).


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 morphology of GHL+ and GHL+/Ask1−/− mice.(A) b/a wave ratio in C57BL/6, Ask1−/−, GHL+, and GHL+/Ask1−/− mice. (B) Representative sections of retinas from 16 week old C57BL/6, Ask1−/−, GHL+ and GHL+/Ask1−/− mice. GHL+ and GHL+/Ask1−/− retinas had shortened OS (arrowheads). (C) Mean number of photoreceptor nuclei per column counted in the ONL. Error bars: ± SD. OPL: outer plexiform layer, ONL: outer nuclear layer, OS: outer segment. Scale bar 50 µm. (D) The variance in the number of photoreceptor nuclei per column counted in different zones of the retina in GHL+ and GHL+/Ask1−/− mice, (right panel). Superior zone: 630 µm from the CMZ, central zone: 630 µm from optic nerve, and inferior zone: midpoint of inferior hemisphere.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0083871-g010: Age related changes in retinal function and morphology of GHL+ and GHL+/Ask1−/− mice.(A) b/a wave ratio in C57BL/6, Ask1−/−, GHL+, and GHL+/Ask1−/− mice. (B) Representative sections of retinas from 16 week old C57BL/6, Ask1−/−, GHL+ and GHL+/Ask1−/− mice. GHL+ and GHL+/Ask1−/− retinas had shortened OS (arrowheads). (C) Mean number of photoreceptor nuclei per column counted in the ONL. Error bars: ± SD. OPL: outer plexiform layer, ONL: outer nuclear layer, OS: outer segment. Scale bar 50 µm. (D) The variance in the number of photoreceptor nuclei per column counted in different zones of the retina in GHL+ and GHL+/Ask1−/− mice, (right panel). Superior zone: 630 µm from the CMZ, central zone: 630 µm from optic nerve, and inferior zone: midpoint of inferior hemisphere.
Mentions: At 28 weeks, the maximal b-wave amplitude (484±117 µV) declined by 50% (p<0.001) of the 4 weeks value in GHL+/Ask1−/− mice (Fig. 9B). Between 4–28 weeks, the maximum b-wave amplitudes were 14–57% higher (p<0.01) in GHL+/Ask1−/− compared to GHL+ mice. Regression of b-wave amplitudes with age was −22.1±3.11 µV/week in GHL+/Ask1−/− mice (Fig. 9B). The rate of decline in b-wave responses was similar in GHL+ and GHL+/Ask1−/− but faster than C57BL/6, Ask1−/− control mice. However, there were significant differences in maximal b-wave amplitudes in GHL+ and GHL+/Ask1−/− mice compared to control mice. To assess signal transmission through the retina we determined the b/a ratio of GHL+/Ask1−/− mice (Fig. 10A). The b/a ratio was similar between C57BL/6 and Ask1−/− mice (Fig. 10A). In GHL+/Ask1−/− mice, the b/a ratio was higher than control C57BL/6 and Ask1−/− animals, but was comparable to GHL+ mice (p>0.05) (Fig. 10A).

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