Potential way to halt blinding macular degeneration identified. Dicer1 knockdown induces accumulation of alu rna in human rpe cells and alulike b1 and b2 rnas in mouse rpe. Dicer1 deficiency is implicated in retinal pigmented epithelium rpe degeneration in atrophic agerelated macular degeneration amd. The most common type of macular degeneration, about 85 to 90 percent of cases, is the dry atrophic type. It begins as a dry form, and progresses to a wet form as blood vessels inappropriately grow into damaged retinal tissue. Dicer1 deficiency induces accumulation of cytotoxic alu rna, which in turn induces tlrindependent activation of the nlrp3 inflammasome 4.
Dicer1 gene therapy as a treatment for agerelated macular degeneration. Geographic atrophy ga, an untreatable advanced form of agerelated macular degeneration, results from retinal pigmented epithelium rpe cell degeneration. Our recent work highlighted another important role for dicer1 in healthy cell. Dicers role in this disease became apparent after it was discovered that affected patients showed decreased levels of dicer in their retinal pigment epithelium rpe. New research shows link between dry and wet amd macular. This missing protein may have an effect in the cause and progression of both the wet and dry forms the disease.
Alu rna accumulation due to dicer1 deficiency in the retinal pigmented epithelium rpe is implicated in geographic atrophy ga, an advanced form of agerelated macular degeneration that causes blindness in millions of individuals. Agerelated macular degeneration armd is the most common cause of irreversible vision loss in the developed world. Deficiency of the dicer enzyme in retinal cells linked to. Dicer1 deficit induces alu rna toxicity in agerelated macular degeneration hiroki kaneko, university of kentucky sami dridi, university of kentucky valeria tarallo, university of kentucky bradley d. Alu rna is increased in the rpe of humans with ga, and this pathogenic rna induces human rpe cytotoxicity and rpe degeneration in mice. Mice with dicer knocked out, lacking dicer only in their rpe, exhibited similar symptoms. Their article, dicer1 deficit induces alu rna toxicity in agerelated macular degeneration, was published online by the journal nature on feb. Age related macular degeneration is a prominent cause of blindness in developed countries. Agerelated means that it often happens in older people. Age related macular degeneration clue discovered bbc news. Agerelated macular degeneration affects 500,000 people in the uk and is incurable. Although the exact mechanism of this association is not fully known, the activation of the nlrp3. Agerelated macular degeneration amd is an eye disease that can blur the sharp, central vision you need for activities like reading and driving.
Here we show that the microrna mirnaprocessing enzyme dicer1 is reduced in the rpe of humans with ga, and that conditional ablation of dicer1, but not seven other. Oxidative stress due to dicer1 depletion may underline the neurodegeneration in the central nervous system and degeneration of retinal pigment epithelial cells in geographic atrophy form of agerelated macular degeneration. Fortunately, most patients with amd can keep good vision for their entire lives, and even those who lose their central vision almost always maintain their side, or peripheral vision. Studying agerelated macular degeneration using animal models. Macular means it affects a part of your eye called the macula. Its the leading cause of severe vision loss in people over age 60. The study in the journal nature found an enzyme known as dicer1 that stops functioning, resulting in the illness. Agerelated macular degeneration national eye institute. Although the exact mechanism of this association is not fully known, the activation of the nlrp3 inflammasome, maturation of caspase1 and disruption in mitochondrial homeostasis in rpe cells were shown as critical for it. Here we show that dicer1 deficit or alu rna exposure activates the nlrp3. Here we show that the microrna mirnaprocessing enzyme dicer1 is reduced in the rpe of humans with ga, and that conditional ablation of dicer1, but not seven other mirnaprocessing. Agerelated macular degeneration results from a combination of genetic and environmental factors. Nonexudative dry agerelated macular degeneration amd. The findings come from a study which looked at geographic atrophy, an advanced stage of the.
Approximately 85% to 90% of the cases of macular degeneration are the dry atrophic type, while 1015% are the wet exudative type. Macular degeneration is a common cause of blindness and vision problems among older people. Extensive atrophy of the retinal pigment epithelium rpe leads to severe vision loss and is termed ga, whose. Initial studies showed reduced expression of dicer1 in the macular rpe of patients with ga and that loss of dicer1 in murine rpe caused cell loss. Many of these factors have been identified, but some remain unknown. The photosensitive cells of the macula slowly break down yellow protein deposits called drusen extracellular waste products from metabolism form and accumulate under the retina between the retinal pigmented epithelium. The authors not only proposed a molecular mechanism leading to amd, but also described a new function for the role of the microrna processing. The authors not only proposed a molecular mechanism leading to amd, but also described a new function for the role of the microrna processingenzyme, dicer1. The most severe form of dryamd is geographic atrophy ga which affects an estimated 1 million people in the us. In contrast to neovascular amd, the more common atrophic form of amd is without effective therapy3, 4. Your doctor can check you for agerelated macular degeneration when you see him for a routine eye exam. Here, we report that two independent hypomorphic mouse strains, as well as a separate model of postnatal rpespecific dicer1 ablation, all presented with spontaneous rpe degeneration and choroidal.
Researchers have considered changes in many genes as possible risk factors for agerelated macular degeneration. Dicer1 degrades alu rna, and this digested alu rna cannot induce rpe degeneration in mice. Dicer1 processes micrornas into their bioactive forms and metabolizes rnas from short interspersed nuclear element genetic repeats, principally alu rnas in humans. Agerelated macular degeneration is an eye disease that may get worse over time. Researchers have identified downregulation of dicer1 as a factor in the progression of the condition, and here demonstrate that a gene therapy to increase expression of dicer1 may. There were encouraging findings into the etiology of amd in the march 11 issue of nature by kaneko et al. Dicer1 deficit induces alu rna toxicity in agerelated macular degeneration article pdf available in nature 4717338. Agerelated macular degeneration amd, which is as prevalent as cancer in industrialized countries, is a leading cause of blindness1, 2. Stargardt disease is a form of macular degeneration found in young people, caused by a recessive gene.
In humans with geographic atrophy, a form of untreatable agerelated macular degeneration amd that results in irreversible blindness, dicer1 protein levels in the rpe are reduced. Pdf dicer1 deficit induces alu rna toxicity in age. The beststudied of these genes are involved in a part of the bodys immune. The study in the journal nature found an enzyme known as dicer1 that stops functioning, resulting in. An early diagnosis will let you start treatment that may delay some symptoms or. New research has shown a possible link between both wet and dry agerelated macular degeneration amd and a lack of a protein called dicer1 in the eye. Fowler, university of kentucky won gil cho, university of kentucky mark e.
Dicer1 deficiency in the retinal pigment epithelium rpe was associated with the accumulation of alu transcripts and implicated in geographic atrophy ga, a form of agerelated macular degeneration amd, an eye disease leading to blindness in millions people. These findings reveal a mirnaindependent cell survival function for dicer1 involving retrotransposon transcript degradation, show that alu rna can directly cause human pathology, and identify new targets for a major cause of blindness. Geographic atrophy is a late stage of agerelated macular degeneration amd that causes blindness in millions worldwide characterized by death of the retinal pigmented epithelium rpe. The macula is a part of the eye that is responsible for seeing sharp details directly in the center of the field of vision. Dicer1 is reduced in appswepsen1de9 mice and is regulated. Here, we report that three independent mouse models of dicer1. The pathogenesis of alzheimers disease ad involves the central roles of oxidative stress. Gene therapy discovery offers hope for patients with amd. We previously reported that rpe death is due to a deficiency in the enzyme dicer1, which leads to accumulation of toxic alu rna. Dicer1 deficit induces alu rna toxicity in agerelated. Armd is associated with the presence of drusen, without visual loss early in the disease, and often progresses to retinal atrophy and central retinal degeneration with associated loss of central vision.
The mechanism of alu rnainduced cytotoxicity is unknown. Insight into dicer1 revealed in macular degeneration. Chronic dicer1 deficiency promotes atrophic and neovascular outer retinal pathologies in mice, proceedings of the national academy of sciences 2020. Dicer1alu rna dysmetabolism induces caspase8mediated. Uk experts said it had the potential to be an important breakthrough. Dicer1 gene therapy as a treatment for agerelated macular. Macular degeneration is also called agerelated macular degeneration, or amd.
This paper finds that dicer1, which processes mirna precursors, is reduced in rpe from. What to expect when you receive the diagnosis of age. Dicer1, encoded by the dicer1 gene in humans, is a type iii ribonuclease rnase best known for its role in processing precursor micrornas premirnas into mature mirnas that are involved in posttranscriptional gene regulation 1, 2. Dryage related macular degeneration is the only major ophthalmic disease with no approved treatment and is one of most common causes of vision loss worldwide. Agerelated macular degeneration is a common form of vision loss. Many patients are frightened of losing vision or going blind when they are told they have agerelated macular degeneration amd. Geographic atrophy is a blinding form of agerelated macular degeneration characterized by retinal pigmented epithelium rpe death. Concurrent with this discovery, ambatis laboratory developed two promising therapies for the prevention of the condition. The newspaper said researchers have found that the lack of a protective protein, called dicer1, is behind one form of agerelated macular degeneration amd.
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