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PubMed2002

Canine inherited retinal degenerations: update on molecular genetic research and its clinical application.

Inherited retinal degenerations in the dog include generalised progressive retinal atrophy, retinal pigment epithelial dystrophy, congenital stationary night blindness and day blindness (hemeralopia). The clinical phenotype and pathology of these diseases closely resemble some types of human inherited retinal degeneration, in particular retinitis pigmentosa, one of the most common inherited causes of blindness in man. Molecular genetic investigations aim to identify the genetic mutations underlying the canine inherited retinal degenerations. Two major research strategies, candidate gene analysis and linkage analysis, have been used. To date, candidate gene analysis has definitively identified the genetic mutations underlying nine inherited retinal degenerations, each in a different breed of dog, and linkage studies have identified genetic markers for a further retinal degeneration which is found in at least six different breeds. This review outlines the research strategy behind candidate gene and linkage studies and summarises recent results in the search for genetic causes of canine inherited retinal degenerations. The aim is to increase awareness of this rapidly changing field and to show how the research can be used to develop genetic tests for these diseases and thereby reduce the incidence of inherited eye disease in dogs.

Animals↗

PubMed2003

Modulating sphingolipid biosynthetic pathway rescues photoreceptor degeneration.

Mutations in proteins of the Drosophila phototransduction cascade, a prototypic guanine nucleotide-binding protein-coupled receptor signaling system, lead to retinal degeneration and have been used as models to understand human degenerative disorders. Here, modulating the sphingolipid biosynthetic pathway rescued retinal degeneration in Drosophila mutants. Targeted expression of Drosophila neutral ceramidase rescued retinal degeneration in arrestin and phospholipase C mutants. Decreasing flux through the de novo sphingolipid biosynthetic pathway also suppressed degeneration in these mutants. Both genetic backgrounds modulated the endocytic machinery because they suppressed defects in a dynamin mutant. Suppression of degeneration in arrestin mutant flies expressing ceramidase correlated with a decrease in ceramide levels. Thus, enzymes of sphingolipid metabolism may be suitable targets in the therapeutic management of retinal degeneration.

Acyltransferases↗

PubMed2003

Lutein and zeaxanthin status and risk of age-related macular degeneration.

PURPOSE: To investigate the relation between plasma concentrations of lutein and zeaxanthin and age-related macular degeneration in a group of elderly men and women. METHODS: The Wisconsin Age-Related Maculopathy Grading System was used to grade features of early and late macular degeneration in 380 men and women, aged 66 to 75 years, from Sheffield, United Kingdom. Fasting blood samples were taken to assess plasma concentrations of lutein and zeaxanthin. RESULTS: Risk of age-related macular degeneration (early or late) was significantly higher in people with lower plasma concentrations of zeaxanthin. Compared with those whose plasma concentrations of zeaxanthin were in the highest third of the distribution, people whose plasma concentration was in the lowest third had an odds ratio for risk of age-related macular degeneration of 2.0 (95% confidence interval [CI] 1.0-4.1), after adjustment for age and other risk factors. Risk of age-related macular degeneration was increased in people with the lowest plasma concentrations of lutein plus zeaxanthin (odds ratio [OR] 1.9, 95% CI 0.9-3.5) and in those with the lowest concentrations of lutein (OR 1.7, 95% CI 0.9-3.3), but neither of these relations was statistically significant. CONCLUSIONS: These findings provide support for the view that zeaxanthin may protect against age-related macular degeneration.

Aged↗

PubMed2006

TNF-alpha-induced optic nerve degeneration and nuclear factor-kappaB p65.

PURPOSE: To characterize a model of optic nerve axonal degeneration induced by tumor necrosis factor (TNF)-alpha and to determine the role of nuclear factor (NF)-kappaB p65 in axonal degeneration. METHODS: Groups of rats were euthanatized at 1 day, 1 or 2 weeks, or 1 or 2 months after intravitreal injection of TNF-alpha. Morphometric analyses of neurofilament- or Thy-1-positive cells, retinal ganglion cells (flat preparations stained with cresyl violet or retrograde labeling with a neurotracer), the number of axons, immunostaining for myelin basic protein, and TUNEL assays were performed. Levels of NF-kappaB p65 protein in retina and optic nerve were determined by Western blot analysis and immunohistochemistry. The effects of antisense oligodeoxynucleotide (AS ODN) against NF-kappaB p65 and helenalin, an inhibitor of NF-kappaB p65 activation, on TNF-alpha-induced optic nerve degeneration were determined by counting the number of axons. RESULTS: Intravitreal injections of TNF-alpha induced obvious axonal loss and extensive degeneration of the axons from 2 weeks to 2 months after injection, whereas significant retinal ganglion cell loss was noted only at 2 months after injection. NF-kappaB p65 was increased in the optic nerve but not in the retina and was found to colocalize with ED-1 and Iba1, markers of microglia. Inhibition of NF-kappaB p65 with AS ODN or helenalin significantly ameliorated the effects of TNF-alpha-mediated axonal loss. CONCLUSIONS: TNF-alpha causes axonal degeneration with probable delayed loss of retinal ganglion cell bodies. NF-kappaB p65 may play a pivotal role in axonal degeneration, with the possible involvement of microglial cells.

Animals↗

PubMed2001

Comparison of apraxia in corticobasal degeneration and progressive supranuclear palsy.

OBJECTIVE: To describe ideomotor apraxia in patients with corticobasal degeneration and those with progressive supranuclear palsy, two parkinsonian disorders that are often misdiagnosed due to the overlap in their clinical features, and to determine whether systematic apraxia testing is useful for differential diagnosis. METHODS: Fourteen patients fulfilling National Institute of Neurological Disorders and Stroke-Society for Progressive Supranuclear Palsy clinical criteria for progressive supranuclear palsy, 13 patients fulfilling modified Lang criteria for corticobasal degeneration, and 12 normal healthy control subjects were given the Test of Oral and Limb Apraxia, which was scored according to the Florida Apraxia Battery for occurrence of various types of apraxic errors. RESULTS: Both patients with progressive supranuclear palsy and corticobasal degeneration committed a greater number of apraxic errors than normal healthy control subjects on both transitive and intransitive tasks (p < 0.001 in both cases), but apraxia was much more severe in patients with corticobasal degeneration than progressive supranuclear palsy (p < 0.001). The index of apraxia severity, in combination with the assessment of the two key features of progressive supranuclear palsy (falls and vertical gaze palsy), correctly classified all patients. CONCLUSIONS: Patients with corticobasal degeneration show more severe ideomotor apraxia than patients with progressive supranuclear palsy, and systematic assessment of ideomotor apraxia facilitates the differential diagnosis between patients with progressive supranuclear palsy and those with corticobasal degeneration.

Aged↗

PubMed1993

Unilateral atrophy of the optic nerve associated with retrograde and anterograde degenerations in the visual pathways in Slc: Wistar rats.

Unilateral degenerative atrophy of the optic nerve (ON) occurred in 6 of 80 male and 4 of 80 female Slc: Wistar rats. Two of these cases completely lost the intracranial portion of the unilateral ON and the remainder had the small ON. The optic disc and ON were located histologically in the posterior pole of the eyeball of 2 rats with no intracranial ON. ON lesions in all cases were characterized by a reduced number of axons with a small number of myelinated axons and marked astrogliosis. There were also swelling, fragmentation and spheroid formation of axons, as well as thickening of the connective tissue sheaths and vessel walls in the ON. One side of the optic chiasma and optic tract contralateral to the affected ON reduced in volume, became degenerated and were accompanied by gliosis. Focal or diffuse degeneration of the retina was observed in the eyeballs with affected ON. Retinal ganglion cells decreased in the number showing chromatolysis. These retinae became thin and developed degeneration of both inner and outer portions with sclerotic changes in the retinal vessels. The ophthalmic and ciliary arteries in the eyeballs with affected ON often developed proliferative or occlusive endoarteritis, suggesting that retinal lesions may have resulted not only from axonal degeneration in the ON but also from ischemia. Histologic lesions suggestive of transneuronal degeneration were found in the contralateral lateral geniculate body and rostral colliculus. Based on the data presented, it was presumed that a primary lesion may have been induced in the ON by a circulatory disturbance and followed by retrograde and anterograde degenerations in the visual pathways.

Animals↗

PubMed2004

Constitutive overexpression of human erythropoietin protects the mouse retina against induced but not inherited retinal degeneration.

Elevation of erythropoietin (Epo) concentrations by hypoxic preconditioning or application of recombinant human Epo (huEpo) protects the mouse retina against light-induced degeneration by inhibiting photoreceptor cell apoptosis. Because photoreceptor apoptosis is also the common path to cell loss in retinal dystrophies such as retinitis pigmentosa (RP), we tested whether high levels of huEpo would reduce apoptotic cell death in two mouse models of human RP. We combined the two respective mutant mouse lines with a transgenic line (tg6) that constitutively overexpresses huEpo mainly in neural tissues. Transgenic expression of huEpo caused constitutively high levels of Epo in the retina and protected photoreceptors against light-induced degeneration; however, the presence of high levels of huEpo did not affect the course or the extent of retinal degeneration in a light-independent (rd1) and a light-accelerated (VPP) mouse model of RP. Similarly, repetitive intraperitoneal injections of recombinant huEpo did not protect the retina in the rd1 and the VPP mouse. Lack of neuroprotection by Epo in the two models of inherited retinal degeneration was not caused by adaptational downregulation of Epo receptor. Our results suggest that apoptotic mechanisms during acute, light-induced photoreceptor cell death differ from those in genetically based retinal degeneration. Therapeutic intervention with cell death in inherited retinal degeneration may therefore require different drugs and treatments.

Animals↗

PubMed2006

Locus ceruleus degeneration promotes Alzheimer pathogenesis in amyloid precursor protein 23 transgenic mice.

Locus ceruleus (LC) degeneration and loss of cortical noradrenergic innervation occur early in Alzheimer's disease (AD). Although this has been known for several decades, the contribution of LC degeneration to AD pathogenesis remains unclear. We induced LC degeneration with N-(2-chloroethyl)-N-ethyl-bromo-benzylamine (dsp4) in amyloid precursor protein 23 (APP23) transgenic mice with a low amyloid load. Then 6 months later the LC projection areas showed a robust elevation of glial inflammation along with augmented amyloid plaque deposits. Moreover, neurodegeneration and neuronal loss significantly increased. Importantly, the paraventricular thalamus, a nonprojection area, remained unaffected. Radial arm maze and social partner recognition tests revealed increased memory deficits while high-resolution magnetic resonance imaging-guided micro-positron emission tomography demonstrated reduced cerebral glucose metabolism, disturbed neuronal integrity, and attenuated acetylcholinesterase activity. Nontransgenic mice with LC degeneration were devoid of these alterations. Our data demonstrate that the degeneration of LC affects morphology, metabolism, and function of amyloid plaque-containing higher brain regions in APP23 mice. We postulate that LC degeneration substantially contributes to AD development.

Alzheimer Disease↗

PubMed2001

Watery and dark axons in Wallerian degeneration of the opossum's optic nerve: different patterns of cytoskeletal breakdown?

In this paper we report a qualitative morphological analysis of Wallerian degeneration in a marsupial. Right optic nerves of opossums Didelphis marsupialis were crushed with a fine forceps and after 24, 48, 72, 96 and 168 hours the animals were anaesthetized and perfused with fixative. The optic nerves were immersed in fixative and processed for routine transmission electron microscopy. Among the early alterations typical of axonal degeneration, we observed nerve fibers with focal degeneration of the axoplasmic cytoskeleton, watery degeneration and dark degeneration, the latter being prevalent at 168 hours after crush. Our results point to a gradual disintegration of the axoplasmic cytoskeleton, opposed to the previous view of an "all-or-nothing" process (Griffin et al 1995). We also report that, due to an unknown mechanism, fibers show either a dark or watery pattern of axonal degeneration, as observed in axon profiles. We also observed fibers undergoing early myelin breakdown in the absence of axonal alterations.

Animals↗

PubMed2006

Photoreceptor cell apoptosis in the retinal degeneration of Uchl3-deficient mice.

UCH-L3 belongs to the ubiquitin C-terminal hydrolase family that deubiquitinates ubiquitin-protein conjugates in the ubiquitin-proteasome system. A murine Uchl3 deletion mutant displays retinal degeneration, muscular degeneration, and mild growth retardation. To elucidate the function of UCH-L3, we investigated histopathological changes and expression of apoptosis- and oxidative stress-related proteins during retinal degeneration. In the normal retina, UCH-L3 was enriched in the photoreceptor inner segment that contains abundant mitochondria. Although the retina of Uchl3-deficient mice showed no significant morphological abnormalities during retinal development, prominent retinal degeneration became manifested after 3 weeks of age associated with photoreceptor cell apoptosis. Ultrastructurally, a decreased area of mitochondrial cristae and vacuolar changes were observed in the degenerated inner segment. Increased immunoreactivities for manganese superoxide dismutase, cytochrome c oxidase I, and apoptosis-inducing factor in the inner segment indicated mitochondrial oxidative stress. Expression of cytochrome c, caspase-1, and cleaved caspase-3 did not differ between wild-type and mutant mice; however, immunoreactivity for endonuclease G was found in the photoreceptor nuclei in the mutant retina. Hence, loss of UCH-L3 leads to mitochondrial oxidative stress-related photoreceptor cell apoptosis in a caspase-independent manner. Thus, Uchl3-deficient mice represent a model for adult-onset retinal degeneration associated with mitochondrial impairment.

Animals↗

PubMedDate not supplied

Effect of airways sensory C fiber network degeneration on airways permeability and responsiveness.

The effect of sensory nerve C fiber network degeneration on airways permeability and responsiveness was studied in guinea pigs. Degeneration of the C fiber sensory network was produced by injecting capsaicin in solvent (total dose 50 mg/kg) into neonatal animals (n = 29) with littermate animals (n = 30) treated with solvent alone serving as controls. Sensory nerve depletion was established by comparing tracheal strips from both groups of animals in vitro. When the animals reached between 400 and 500 g body weight, airways permeability to fluorescein isothiocyanate dextran (FITC-D) and airways responsiveness to a graded dose of aerosolized histamine were measured. The data show that degeneration of the C fiber network had no effect on the airways responsiveness to histamine. They also show that degeneration of the C fiber network produced a significant (P less than or equal to .01) increase in airways reactivity [0.36 +/- 0.08 cm H2O/mL s-1 (mean +/- SEM)] following cigarette smoke exposure compared with control (0.11 +/- 0.04) or control-smoke-exposed animals (0.10 +/- 0.02). Degeneration of the C fiber network did not affect the increased permeability seen following cigarette smoke exposure (capsaicin pretreated 39.8 +/- 9.1 and control pretreated 28.4 +/- 7.9 (micrograms)(min)/mg). We conclude that degeneration of the C fiber network is associated with increased rather than decreased airways responsiveness in guinea pigs exposed to cigarette smoke.

Airway Resistance↗

PubMedDate not supplied

Rod ERGs in children with hereditary retinal degeneration.

Rod ERGs were obtained over a broad range of stimulus intensities from young patients with retinitis pigmentosa and progressive cone-rod degeneration. Intensity-response functions suggest that children with retinitis pigmentosa have reductions in the number of functioning rods and that surviving rods generating the ERG have reduced sensitivity. Children with cone-rod degeneration also have reduced numbers of rods, but the remaining rods have normal sensitivity. These findings suggest that the underlying mechanisms of rod degeneration differ in these two forms of disease and demonstrate that insights into the pathogenesis of hereditary retinal degeneration can be obtained by testing children. The ability to distinguish between retinitis pigmentosa and cone-rod degeneration in children is also important because of differences in the rates of progression between the two classes of progressive retinal degeneration.

Child↗

PubMed2000

Influence of experimental chronic high-pressure glaucoma on age-related macular degeneration in rhesus monkeys.

PURPOSE: To assess prospectively whether development of age-related macular degeneration is influenced by experimentally induced chronic high-pressure glaucoma, and whether age-related macular degeneration influences the appearance of the optic nerve head in experimental chronic high-pressure glaucoma in older rhesus monkeys. METHODS: The longitudinal study included 102 eyes of 52 rhesus monkeys. The total study group was divided into a group with experimentally induced unilateral chronic high-pressure glaucoma (n = 40 eyes) and a normal control group (n = 62 eyes). Additionally, arterial hypertension and atherosclerosis were experimentally induced in both study groups in a similar percentage of monkeys. Mean monkey age at the end of the study was 19.6 +/- 3.1 years (range, 13-24 years). The macular region, optic disc, and retinal nerve fiber layer were morphometrically evaluated by color wide-angle fundus photographs taken at baseline and at the end of the study. RESULTS: The degree of age-related macular degeneration, measured as number and area of drusen in the foveal and extrafoveal region of the macula, did not differ significantly between the two study groups. In the glaucomatous group, the degree of macular degeneration was statistically independent of the development of parapapillary atrophy, loss of neuroretinal rim, and decrease in the visibility of the retinal nerve fiber layer. CONCLUSIONS: Development of age-related macular degeneration in rhesus monkeys is independent of concomitant chronic high-pressure glaucoma, including the development of glaucomatous parapapillary chorioretinal atrophy. Conversely, age-related macular degeneration does not markedly influence the course of experimental chronic high-pressure glaucoma or the development of parapapillary atrophy in monkeys.

Animals↗

PubMed2001

Electrically active axons degenerate when exposed to nitric oxide.

Axonal degeneration is a major cause of permanent deficit in inflammatory neurological diseases such as multiple sclerosis. Axons undergo degeneration specifically at the site of the inflammatory lesions, suggesting that locally produced inflammatory factors mediate the phenomenon. One such factor is nitric oxide (NO), which we have previously reported can cause reversible conduction block in axons. Here we confirm these observations and extend them to show that axons exhibit the early stages of wallerian degeneration if they are conducting impulses at physiological frequencies while they are exposed to the low micromolar concentrations of NO that are likely to occur at sites of inflammation. Rat dorsal roots were concurrently exposed in vivo to both NO and sustained impulse activity at 1, 50, or 100 Hz. Although our in vivo observations necessarily focused on the more acute responses, morphological examination of exposed roots at the end of the recording period revealed nodal and paranodal changes consistent with acute wallerian degeneration in roots stimulated at 50 or 100 Hz. This interpretation was confirmed in a few experiments that were prolonged to permit more obvious indicators of degeneration to develop. In these experiments the formation of myelin ovoids and frank axonolysis occurred in more than 95% of fibers. Roots stimulated at only 1 Hz appeared normal. We propose that the combination of normal impulse traffic and NO at sites of inflammation may cause axonal degeneration and that electrical activity may therefore be an important factor in causing permanent disability in patients with neuroinflammatory disorders.

Action Potentials↗

PubMed2001

[Myopia: frequency of lattice degeneration and axial length].

OBJECTIVE: To evaluate the relationship between lattice retinal degeneration and axial length of the eye in different grades of myopia. MATERIAL AND METHODS: A sample of 200 eyes from 124 myopic patients was collected by chance. The average age was 34.8 years (20-50 years) and the myopia was between 0.5 and 20 diopters (D). The eyes were grouped according to the degree of refraction defect, the mean axial length of each group (Scan A) and the frequency of lattice retinal degeneration and the relationship between these variables was studied. The possible influence of age on our results was also considered. For the statistical analysis, the SAS 6.07 program with the variance analysis for quantitative variables, and chi(2) test for qualitative variables with a 5% significance were used. A multivariable linear regression model was also adjusted. RESULTS: The highest frequency of lattice retinal degeneration occurred in those myopia patients having more than 15 D, and also in the group of myopia patients between 3 and 6 D, but this did not show statistical significance when compared with the other myopic groups. If the axial length is assessed, a greater frequency of lattice retinal degeneration is also found when the axial length is 25-27 mm and 29-30 mm, which correspond, respectively, to myopias between 3-10 D and more than 15 D. When the multivariable linear regression model was adjusted, the axial length showed the existence of lattice retinal degeneration (beta 0.41 mm; p=0.08) adjusted by the number of diopters (beta 0.38 mm; p<0.001). The determination coefficient (r(2)) was also 0.86. CONCLUSIONS: The highest number of cases of lattice retinal degeneration was found for myopias with axial eye length between 29-30 mm (more than 15 D), and 25-27 mm (between 3-10 D).

Adult↗

PubMed2000

[The attractive effects of nerve regeneration chamber fluid and degenerated nerve segments on the growth and the migration of the cocultured dorsal root ganglion neuron].

OBJECTIVES: We intended in this study to investigate the neurotropic effects of regeneration chamber fluid (RCF) and the degenerated nerve segments from distal of the regeneration chamber on the dorsal root ganglion (DRG). METHODS: The capillary model was first tested for its reliability to form concentration gradient with a dye being contained in the capillaries. The tissue culture in RCF test was divided into two groups each with 8 DRGs implanted in 8 dishes. RCF was contained in capillaries inserted down to the bottom of the dishes with their lower ends at a distance of about 1 mm to the DRGs in the experimental group, and DMEM media was contained in the control group. Segments of degenerated sciatic nerve from distal of the regeneration chamber were implanted with DRGs at a distance of about 0.5 - 1 mm in the coculturing experiment. DRGs were observed for the direction of the growth of the cells and the fibres. RESULTS: While the capillary containing the dye was put down to the bottom of the culture dish coated with a piece of nylon pad, the red color slowly disseminated with heavier staining in the center and lighter staining in the peripheral portion. We believe this pattern of shade could simulate the concentration gradient of tropic factors in this model. There were significantly more nerve fibres growing from the DRGs towards the capillaries in 6 of the 8 dishes in the experimental group after 72 hours of culture. The tissue and nerve fibers grew evenly in the control group. 76.5% of all the nerve fibres were growing in the direction facing the degenerated nerve segments after 12 hours of coculturing, and only 33.3% of the nerve fibres growing in that direction in the control group. Cells from the DRGs migrated towards the degenerated nerve segments, yet they tended to avoid the normal nerve segments. The migration index of the cells was 0.98 in average in the coculturing experiment with the degenerated nerve segments, but only 0.43 in average with the normal nerve coculturing. CONCLUSION: The capillary model was effective in studying the chemotactic growth of nerve tissue. RCF and the degenerated nerve segments had definite neurotropic effects on DRGs tissue.

Animals↗

PubMed2002

Cone neurite sprouting: an early onset abnormality of the cone photoreceptors in the retinal degeneration mouse.

PURPOSE: Mutations in many rod genes can cause inherited blinding neurodegeneration in the retina characterized by sequential death of rod and cone photoreceptors. This study was to examine the morphological changes of the cone photoreceptors in retinal degeneration (rd1) mice caused by rod-specific cGMP phosphodiesterase beta-subunit gene mutation and to gain insights into the early cellular events underlying the secondary cone death. METHODS: Transgenic mice that have their living cones labeled by the green fluorescent protein (GFP) transgene and carry the homozygous rd1 mutation were generated, and identified by PCR analysis of the mouse tail DNA and PCR coupled Dde I digestion. The morphology of cone cells in live and fixed retinas from developing and adult mice was examined with fluorescence and scanning laser confocal microscopy. Some fixed mouse retinas were also examined by immunocytochemical staining. Volume images from the confocal three-dimensional (3D) data sets were processed with IMARIS software for 3D view of the detailed cone cell morphology. RESULTS: The cone photoreceptors in the rd1 retinas exhibited a novel process of neurite sprouting, in addition to the general pathological changes of cone degeneration such as shortening and loss of cone outer and inner segments, and loss and death of the cones. The cones gave rise to prominent neurite outgrowth from their axons and synaptic pedicles as well. Most neurites had beaded varicosities along their length and some terminated as bulbous structures. Some cone pedicles showed abnormally elongating and branching processes. The degenerating cones were disorganized, and migrated into the inner nuclear layer. Some cone neurites extended horizontally and appeared to contact the rod bipolar cells, while others projected into the inner plexiform layer. The aberrant cone sprouting started from P8 when rod degeneration generally began, and became evident by P10. In contrast, this abnormal cone neurite sprouting was not observed in the examined control mice that did not carry the rd1 mutation. Double-labeling with cone cell-specific peanut agglutinin confirmed that the fluorescent cells expressing the GFP in the rd1 retinas were indeed the cone photoreceptors. CONCLUSIONS: Cone photoreceptors in the rd1 mice underwent a remarkable process of neurite sprouting that appeared to start before the onset of cone cell death and persisted throughout the course of cone degeneration. This novel process of cone neurite sprouting may be a part of the early cellular events leading to the cone photoreceptor death in retinal degeneration of the rd1 mice.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed2003

Caspase-3 inhibitor reduces apototic photoreceptor cell death during inherited retinal degeneration in tubby mice.

PURPOSE: The tubby mouse, previously suggested as an animal model for the human Usher Syndrome type I, was used in an analysis of pathophysiological processes leading to the inherited retinal degeneration, also shown in Usher syndrome patients. To evaluate pathogenic mechanisms causing retinal degeneration in tubby mice, we examined the time course of apoptotic photoreceptor cell death. Apoptotic pathways were determined by the inhibition of specific caspases in vivo. METHODS: Apoptotic cells were identified during retinal differentiation and degeneration by the TUNEL-method. Apoptotic events were confirmed by DNA-laddering. Intravitreal injection of apoptosis inhibitors was applied to reduce apoptotic photoreceptor cell death in tubby mice. RESULTS: During retinal differentiation there is no apparent difference between tubby and wild type mice in apoptotic events. Between post natal day 16 and 23, apoptosis was detected in the outer nuclear layer of tubby mice retinas, but was absent in control mice. The number of TUNEL-labeled photoreceptor cells peaked at post natal day 19. After this peak of apoptosis, the number of apoptotic photoreceptor cells gradually decreased. While a caspase-1 inhibitor did not reduce the number of apoptotic cells, a specific caspase-3 inhibitor caused a significant decrease of apoptotic photoreceptor cells in the tubby mouse retina. CONCLUSIONS: Apoptosis is necessary for appropriate differentiation of the retina of tubby and wild type mice. In the fully developed tubby mouse retina, apoptotic photoreceptor cell death leads to retinal degeneration. Apoptosis in the tubby mouse retina is mediated by specific activation of members of the caspase-3 family. Caspase-3 inhibition drastically reduces photoreceptor cell death in the degenerating tubby mouse retina and may be a potential tool for therapeutic strategies of retinal degeneration in human Usher patients.

Amino Acid Chloromethyl Ketones↗