Limits...
Necrotic enlargement of cone photoreceptor cells and the release of high-mobility group box-1 in retinitis pigmentosa

View Article: PubMed Central - PubMed

ABSTRACT

Retinitis pigmentosa (RP) refers to a group of inherited retinal degenerations resulting form rod and cone photoreceptor cell death. The rod cell death due to deleterious genetic mutations has been shown to occur mainly through apoptosis, whereas the mechanisms and features of the secondary cone cell death have not been fully elucidated. Our previous study showed that the cone cell death in rd10 mice, an animal model of RP, involves necrotic features and is partly mediated by the receptor interacting protein kinase. However, the relevancy of necrotic cone cell death in human RP patients remains unknown. In the present study, we showed that dying cone cells in rd10 mice exhibited cellular enlargement, along with necrotic changes such as cellular swelling and mitochondrial rupture. In human eyes, live imaging of cone cells by adaptive optics scanning laser ophthalmoscopy revealed significantly increased percentages of enlarged cone cells in the RP patients compared with the control subjects. The vitreous of the RP patients contained significantly higher levels of high-mobility group box-1, which is released extracellularly associated with necrotic cell death. These findings suggest that necrotic enlargement of cone cells is involved in the process of cone degeneration, and that necrosis may be a novel target to prevent or delay the loss of cone-mediated central vision in RP.

No MeSH data available.


Related in: MedlinePlus

Enlargement of the cone cell size in the mouse model of retinitis pigmentosa. (a) Whole-mount staining of the wild-type (WT; left panel) and rd10 mouse retinas at P21 (middle panel) and P42 (right panel) with PNA. The lower panels are higher magnification of peanut agglutinin lectin (PNA)-positive cone cells. Yellow line: the width of the inner segment of each cone cell. Scale bar, 50 μm (upper panel), 10 μm (lower panel). (b, c) Quantification of the density (b) and width (c) of PNA-positive cone cells in WT mice (n=6), rd10 mice at P21 (n=6), and rd10 mice at P42 (n=6). *P<0.05, **P<0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4979449&req=5

fig1: Enlargement of the cone cell size in the mouse model of retinitis pigmentosa. (a) Whole-mount staining of the wild-type (WT; left panel) and rd10 mouse retinas at P21 (middle panel) and P42 (right panel) with PNA. The lower panels are higher magnification of peanut agglutinin lectin (PNA)-positive cone cells. Yellow line: the width of the inner segment of each cone cell. Scale bar, 50 μm (upper panel), 10 μm (lower panel). (b, c) Quantification of the density (b) and width (c) of PNA-positive cone cells in WT mice (n=6), rd10 mice at P21 (n=6), and rd10 mice at P42 (n=6). *P<0.05, **P<0.01.

Mentions: Rd10 mice are an animal model of RP caused by a missense mutation in the Pde6β gene.16 Mutations in this gene have been found in patients with autosomal recessive RP.17Rd10 mice develop progressive rod degeneration beginning around postnatal day 18 (P18), and only a slight proportion of rod cells remains at P28; the number of cone cells gradually decreases thereafter. Using biochemical and genetic techniques, we have previously shown that cone cell death occurs via RIP kinase-mediated necrosis.9 To investigate changes in cone photoreceptor cell density, morphology, and size, we performed whole-mount immunofluorescence for peanut agglutinin lectin (PNA), which selectively binds to the cone inner and outer segment.18 The cone cell density in rd10 mice was comparable to that in wild-type (WT) mice at P21, whereas it was significantly decreased at P42 in the rd10 mice (Figures 1a and b; P<0.05). We next examined the changes in cellular size during cone degeneration. The width of the inner segment of cone cells was significantly increased in the P21 rd10 mice, and further enlarged as the loss of cones progressed by day p42 (Figures 1a and c; P<0.01). These findings suggest that the enlargement of cone cells occurs in an early phase of cone degeneration in rd10 mice and is consistent with the necrotic mechanism of cell loss.


Necrotic enlargement of cone photoreceptor cells and the release of high-mobility group box-1 in retinitis pigmentosa
Enlargement of the cone cell size in the mouse model of retinitis pigmentosa. (a) Whole-mount staining of the wild-type (WT; left panel) and rd10 mouse retinas at P21 (middle panel) and P42 (right panel) with PNA. The lower panels are higher magnification of peanut agglutinin lectin (PNA)-positive cone cells. Yellow line: the width of the inner segment of each cone cell. Scale bar, 50 μm (upper panel), 10 μm (lower panel). (b, c) Quantification of the density (b) and width (c) of PNA-positive cone cells in WT mice (n=6), rd10 mice at P21 (n=6), and rd10 mice at P42 (n=6). *P<0.05, **P<0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4979449&req=5

fig1: Enlargement of the cone cell size in the mouse model of retinitis pigmentosa. (a) Whole-mount staining of the wild-type (WT; left panel) and rd10 mouse retinas at P21 (middle panel) and P42 (right panel) with PNA. The lower panels are higher magnification of peanut agglutinin lectin (PNA)-positive cone cells. Yellow line: the width of the inner segment of each cone cell. Scale bar, 50 μm (upper panel), 10 μm (lower panel). (b, c) Quantification of the density (b) and width (c) of PNA-positive cone cells in WT mice (n=6), rd10 mice at P21 (n=6), and rd10 mice at P42 (n=6). *P<0.05, **P<0.01.
Mentions: Rd10 mice are an animal model of RP caused by a missense mutation in the Pde6β gene.16 Mutations in this gene have been found in patients with autosomal recessive RP.17Rd10 mice develop progressive rod degeneration beginning around postnatal day 18 (P18), and only a slight proportion of rod cells remains at P28; the number of cone cells gradually decreases thereafter. Using biochemical and genetic techniques, we have previously shown that cone cell death occurs via RIP kinase-mediated necrosis.9 To investigate changes in cone photoreceptor cell density, morphology, and size, we performed whole-mount immunofluorescence for peanut agglutinin lectin (PNA), which selectively binds to the cone inner and outer segment.18 The cone cell density in rd10 mice was comparable to that in wild-type (WT) mice at P21, whereas it was significantly decreased at P42 in the rd10 mice (Figures 1a and b; P<0.05). We next examined the changes in cellular size during cone degeneration. The width of the inner segment of cone cells was significantly increased in the P21 rd10 mice, and further enlarged as the loss of cones progressed by day p42 (Figures 1a and c; P<0.01). These findings suggest that the enlargement of cone cells occurs in an early phase of cone degeneration in rd10 mice and is consistent with the necrotic mechanism of cell loss.

View Article: PubMed Central - PubMed

ABSTRACT

Retinitis pigmentosa (RP) refers to a group of inherited retinal degenerations resulting form rod and cone photoreceptor cell death. The rod cell death due to deleterious genetic mutations has been shown to occur mainly through apoptosis, whereas the mechanisms and features of the secondary cone cell death have not been fully elucidated. Our previous study showed that the cone cell death in rd10 mice, an animal model of RP, involves necrotic features and is partly mediated by the receptor interacting protein kinase. However, the relevancy of necrotic cone cell death in human RP patients remains unknown. In the present study, we showed that dying cone cells in rd10 mice exhibited cellular enlargement, along with necrotic changes such as cellular swelling and mitochondrial rupture. In human eyes, live imaging of cone cells by adaptive optics scanning laser ophthalmoscopy revealed significantly increased percentages of enlarged cone cells in the RP patients compared with the control subjects. The vitreous of the RP patients contained significantly higher levels of high-mobility group box-1, which is released extracellularly associated with necrotic cell death. These findings suggest that necrotic enlargement of cone cells is involved in the process of cone degeneration, and that necrosis may be a novel target to prevent or delay the loss of cone-mediated central vision in RP.

No MeSH data available.


Related in: MedlinePlus