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Fighting Blindness: Scientists Bring a Key Protein into Focus PDF
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Ophthalmology and Optometry
Wednesday, 15 March 2017

TSRI BuildingScientists from the Florida campus of The Scripps Research Institute (TSRI) have discovered how a protein called α2δ4 establishes proper vision. Their research helps explain why mutations in the gene encoding α2δ4 lead to retinal dystrophy, a disease characterized by defective color vision and night blindness. To study how this protein supports vision, the researchers modeled retinal dystrophy in mice. Like humans, mice lacking α2δ4 succumbed to the disease and their vision was compromised.

“Much of our work is driven by desire to understand what goes awry in a range of blinding conditions,” explained TSRI Professor Kirill A. Martemyanov, senior author of the new study. “Now we have found a molecule that plays a key role in allowing photoreceptors to plug into the neural circuit and transmit the light signals they receive to the brain.”

Our vision depends on two types of photoreceptors in the light-sensitive layer of eye called the retina. Rods photoreceptors detect photons at the lowest levels of light and support night vision, and cone photoreceptors sense bright light and discriminate between colors. Both rods and cones must wire into a neural circuit of the retina to send information to the brain.

Martemyanov and his colleagues are studying the neural connections that make vision possible. In a previous study, the researchers identified a novel cell-adhesion protein called ELFN1 that rods use for making contacts with their partners, called bipolar neurons. However, how ELFN1 accomplishes the task of photoreceptor wiring was not clear.

In the new study, experiments spearheaded by TSRI Research Associate Yuchen Wang of the Martemyanov laboratory showed that this connectivity requires α2δ4 to join a structure, called a higher order macromolecular complex, with ELFN1 and other proteins called calcium channels. These calcium channels trigger the release of the chemical messenger glutamate, which photoreceptors use for communicating with bipolar neurons.

In short, Wang explained, without both α2δ4 and the other calcium channels in the macromolecular complex, rods cannot connect to the neural circuit. “We found that α2δ4 is essential for organizing the presynaptic compartment of rod photoreceptors,” he said.

Strikingly, eliminating the corresponding gene for α2δ4 in a mouse model interrupted the transmission of light signals from photoreceptors to the brain without affecting the ability to detect light. “It’s like you are trying to make a phone call—and your phone is fully functional—but you are not heard because there is no signal,” Martemyanov said.

Cones seemed to handle the lack of α2δ4 only slightly better. Without the α2δ4, mice failed to see under dim light conditions and could not navigate a maze in low light due to their dysfunctional rods. Their cones were affected too, but they could still send some weak signals through to the brain.

“Their dim-light vision was completely abolished,” said Martemyanov. “And the signal from the cones could barely make it.”

The study was published online recently in the journal Neuron.

 
Eyes Hold Clues To Future Narrowing of Leg Vessels PDF
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Ophthalmology and Optometry
Tuesday, 14 March 2017

EyeChanges in tiny blood vessels of the eye may predict a higher risk of later narrowing in the large blood vessels in the legs, according to a study presented at the American Heart Association's Epidemiology and Prevention | Lifestyle and Cardiometabolic Health 2017 Scientific Sessions.

Researchers reported on 9,390 adults participating in the long-term Atherosclerosis Risk in Communities Study, each with retinal photographs taken between 1993-1995, when they did not have peripheral artery disease (PAD). During a 19-year follow-up, 304 developed PAD requiring hospitalization or a procedure to open narrowed leg vessels. Of those, 92 had the most severe form of PAD, called critical limb ischemia (CLI), resulting in ulcers on the leg, gangrene or the need for amputation.

After adjusting for common PAD risk factors, such as diabetes, the investigators found that when scans showed any type of abnormalities in the retina, there was a 2.16 times greater risk of PAD developing during the follow-up period, and a 3.41 times greater risk of CLI. Individual retinal abnormalities -- including bleeding, yellow spots from the breakdown of lipids (hard exudates) and areas of blood protruding from vessels in the back of the eye (microaneurysm) -- were also associated with the risk of PAD or CLI. The associations between retinal damage and PAD were stronger in people with diabetes than those without.

According to the researchers, microvascular abnormalities may impair wound healing or the creation of alternative routes for blood to flow around narrowed leg vessels, leading to more severe PAD.

 
World-first Genetic Clues Point to Risk of Blindness PDF
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Ophthalmology and Optometry
Thursday, 09 March 2017

Bahlo, Scerri, and QuaglieriAustralian scientists have discovered the first evidence of genes involved in Macular Telangiectasia type 2 (MacTel), a currently incurable eye disease that can lead to blindness.

The team’s findings established five key regions – or loci – in the genome most likely to influence a person’s risk of developing MacTel. The finding will enable researchers to better understand the disease and look for ways to prevent or stop its progression.

The study, published in Nature Genetics, was an international collaboration led by bioinformaticians Professor Melanie Bahlo and Dr Thomas Scerri at Melbourne’s Walter and Eliza Hall Institute of Medical Research.

MacTel is a rare and complex disease that mainly affects people from the age of 40 onwards. The symptoms begin with patients experiencing a loss of central vision crucial for tasks requiring focus, such as driving or reading.

Professor Bahlo said the study involved detailed genetic analysis of MacTel patients from around the world, including Australia, using genome wide association studies (GWAS).

“We analysed more than six million genetic markers and identified five loci across the genome that had similar patterns in people with the disease, but not in the healthy individuals,” Professor Bahlo said.

“These five genetic risk loci are our 'treasure map', telling us where to ‘keep digging’ in order to discover the specific genes implicated in MacTel,” she said.

Professor Bahlo said the team worked with collaborators in London and New York to analyse the genetic data from 476 people with MacTel and 1733 controls [people without the disease].

“We were thrilled when our results were corroborated by two further independent validation studies,” she said.

The analysis also revealed that people with the MacTel genetic risk loci identified in the study had changes in their metabolism, specifically in their glycine and serine levels.

Professor Bahlo said this meant there could be a significant relationship between the level of glycine and serine in the body, and onset of the disease.

“Though the exact link between the disease and glycine and serine is yet to be confirmed, the connection is an exciting clue to help us further explore metabolic abnormalities in people with MacTel,” Professor Bahlo said.

Dr Scerri said the team’s work highlighted crucial points of interest that, with further investigation, could help researchers find a way to prevent the progression of the disease.

“We are continuing to explore the genetic data to try identify the specific genes involved, and the precise genetic variations that are leading to the disease,” Dr Scerri said.

President of the Lowy Medical Research Institute that sponsored the research Professor Martin Friedlander said the work represented a significant advancement in efforts to understand the cause of MacTel.

“We are working towards developing treatments effective in preserving vision in patients with this disease,” he said. 

 
Humans Read Emotions Based On How The Eye Sees PDF
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Ophthalmology and Optometry
Friday, 24 February 2017

Fovea Study GraphicVision scientists have uncovered some of the reasons behind the unusual perceptual properties of the eye’s fovea. Only humans and other primates have this dimple-like structure in their retinas. It is responsible for visual experiences that are rich in colorful spatial detail. Figuring out how the fovea functions is essential to the search for strategies to correct central vision loss, including efforts to design visual prosthetics.

“Diseases such as macular degeneration are much more debilitating than deficits in peripheral eyesight because of the importance of the fovea to everyday vision,” said Dr. Raunak Sinha of the Department of Physiology and Biophysics at the University of Washington (UW) School of Medicine.

The fovea is a specialized region that dominates our visual perception, Sinha explained. It provides more than half of the input from the eyes to the visual cortex of the brain. When you look at a scene an arm’s length away, he said, the fovea subtends a field only about the size of your thumbnail. Your eyes undergo rapid movements to direct the fovea to various parts of the scene.

The absence of a fovea in most mammals, he said, and technical challenges associated with recording from the primate fovea led to a paucity of information about how the fovea operates at the level of cellular circuits. Advanced techniques now show that the fovea's computational architecture and basic visual processing are distinct from other regions of the retina. Located near the optic nerve, the fovea is at its best for fine tasks like reading. Compared to the peripheral retina, however, the fovea is less able to process rapidly changing visual signals. This low sensitivity is what makes us see motion in flipbooks and movies. It’s also what prevents us from seeing flicker when a computer or TV screen refreshes, unless we glance at the screen (especially the old-fashioned CRT monitors) from the corner of our eye, Sinha explained.

Past recordings of foveal output signals in the living eye had demonstrated that the perceptual specializations of foveal vision originated largely in the retina itself, rather than in subsequent brain circuits. Nonetheless, Sinha said, little was known about the cellular and circuitry basis of these functional specializations due to a lack of intracellular recordings from foveal neurons.

The UW and Howard Hughes Medical Center research team recently made the first direct comparisons of the physiological properties of foveal and peripheral retinal neurons and the first correlation between structure and function in the fovea. The project was conducted in the laboratories of Fred Rieke in the UW Department of Physiology and Biophysics and Rachel Wong in the UW Department of Biological Structure. The findings were published in the journal Cell. Their experiments revealed how differences in the cellular and circuit mechanisms of foveal and peripheral retina can account for the well-established differences in their perceptual sensitivities. Specifically, the researchers found that foveal midget ganglion cells (a major class of retinal output neurons) process input and output signals in a manner that shows that they are not smaller versions of their peripheral counterparts. The researchers discovered that the dominant neural circuit in the fovea (the midget pathway) operates effectively independent of any sort of “braking” at the specialized signaling junction called the synapse.

“This was surprising given the central role inhibition plays in every other well-characterized neural circuit, “said Rieke, whose lab explores sensory signal processing at the limits imposed by physics. Sinha and colleagues also compared the responses of the cone photoreceptors – the neurons at the frontline of the visual system. They found that the responses in the fovea are about two-fold slower than those in the periphery. This is nearly identical to the differences between central and peripheral vision in perceiving rapidly changing inputs. The finding suggests that the perceptual differences originate in the cone photoreceptors themselves.

“The novelty of this study is bolstered by a comprehensive structure-function analyses, lacking in previous work on the fovea, using techniques such as particle-mediated gene transfer to study protein expression in a diverse array of ganglion cells,” said Mrinalini Hoon, an acting instructor in biological structure at the UW School of Medicine who contributed to the recent research. These approaches open the door to a wide-range of transient genetic manipulations that will allow scientists to explore properties of other cell types in the fovea.

“Determining the cellular origin of human perception is an important, but rarely realized, goal in neuroscience and biology,” Sinha said. “Our results provide a simple explanation for a salient perceptual observation.”

 
Researchers Find Vitamin B3 Prevents Glaucoma PDF
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Ophthalmology and Optometry
Monday, 20 February 2017

Vitamin B3In mice genetically predisposed to glaucoma, vitamin B3 added to drinking water is effective at preventing the disease, a US research team led by Jackson Laboratory (JAX) Professor and Howard Hughes Medical Investigator Simon W.M. John reports in the journal Science.

The vitamin administration was surprisingly effective, eliminating the vast majority of age-related molecular changes and providing a remarkably robust protection against glaucoma. It offers promise for developing inexpensive and safe treatments for glaucoma patients.

“We wanted to identify key age-related susceptibility factors that change with age in the eye,” John says, “and that therefore increase vulnerability to disease and in particular neuronal disease.” By understanding general age-related mechanism, there is the potential to develop new interventions to generally protect from common age-related disease processes in many people. Conducting a variety of genomic, metabolic, neurobiological and other tests in mice susceptible to inherited glaucoma, compared to control mice, the researchers discovered that NAD, a molecule vital to energy metabolism in neurons and other cells, declines with age.

“There’s an analogy with an old motorbike,” John says. “It runs just fine, but little things get less reliable with age. One day you stress it: you drive it up a steep hill or you go on really long journey and you get in trouble. It's less reliable than a new bike and it’s going to fail with a higher frequency than that new bike.”

The decrease in NAD levels reduces the reliability of neurons’ energy metabolism, especially under stress such as increased intraocular pressure. “Like taking that big hill on your old bike, some things are going to fail more often,” John says. “The amount of failure will increase over time, resulting in more damage and disease progression.”

In essence, the treatments of vitamin B3 (nicotinamide, an amide form of vitamin B3, also called niacinamide) boosted the metabolic reliability of aging retinal ganglion cells, keeping them healthier for longer. “Because these cells are still healthy, and still metabolically robust,” says JAX Postdoctoral Associate Pete Williams, first author of the study, “even when high intraocular pressure turns on, they better resist damaging processes.”

The researchers also found that a single gene-therapy application of Nmnat1 (the gene for an enzyme that makes NAD from nicotinamide) prevented glaucoma from developing in this mouse model. “It can be a problem for patients, especially the elderly, to take their drugs every day and in the correct dose,” Williams says. “So gene therapy could be a one-shot, protective treatment.” He notes that gene therapies, through injections into the eye, have been approved for a handful of very rare, human genetic eye disorders, and their demonstration of an important age-dependent factor may enable gene therapy for more common eye disease.

John says that the team is pursuing clinical partnerships to begin the process of testing the effectiveness of vitamin B3 treatment in glaucoma patients. They are also exploring potential applications for the treatment in other diseases involving neurodegeneration.

 
Myopia Cell Discovered in Retina PDF
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Ophthalmology and Optometry
Friday, 10 February 2017

ON delayed retinal ganglion celScientists of Northwestern University in US have discovered a cell in the retina that may cause myopia when it dysfunctions. The dysfunction may be linked to the amount of time a child spends indoors and away from natural light.

“This discovery could lead to a new therapeutic target to control myopia,” said Greg Schwartz, lead investigator and assistant professor of ophthalmology at Northwestern University Feinberg School of Medicine.

More than a billion people in the world have myopia, whose incidence is rising and is linked to how much time people spend indoors as children. The newly discovered retinal cell — which is highly sensitive to light — controls how the eye grows and develops. If the cell instructs the eye to grow too long, images fail to be focused on the retina, causing nearsighted vision and a lifetime of corrective glasses or contact lenses. 

“The eye needs to stop growing at precisely the right time during childhood,” Schwartz said.

It has long been long known the retina contains a signal to focus the image in the eye, and this signal is important for properly regulating eye growth during childhood.

“But for years no one knew what cell carried the signal,” Schwartz said. “We potentially found the key missing link, which is the cell that actually does that task and the neural circuit that enables this important visual function.”

Schwartz named the cell, “ON Delayed,” in reference to its slow responses to lights becoming brighter. The cell was unique among many other cell types tested in its exquisite sensitivity to whether an image was in focus.

He described the neural circuit as the diagram that reveals how this cell is wired to other cells in the retina to acquire this unique sensitivity.

The indoor light spectrum has high red/green contrast, which activates these clusters of photoreceptors in the human eye, creating the equivalent of an artificial contrast image on the retina. It’s likely the human version of the ON Delayed retinal ganglion cell would be overstimulated by such patterns, causing aberrant over-growth of the eye, leading to myopia, Schwartz said.

The study is published online at Current Biology.

 
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