Scientists from the Florida campus of The Scripps Research Institute 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.
TSRI Professor Kirill A. Martemyanov and his colleagues study 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 this study, experiments 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, as the authors explain, without both α2δ4 and the other calcium channels in the macromolecular complex, rods cannot connect to the neural circuit.
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.
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.
Going forward, Dr. Martemyanov and his team plan to study whether manipulating α2δ4 could help photoreceptors transmit their signals and maintain connectivity to stay functional longer in models of age-related vision loss, such as age-related macular degeneration.
The researchers also think that wiring factors such as α2δ4 and ELFN1 could also help researchers address a current challenge in using stem cells to correct vision loss.
Dr. Martemyanov explained that current efforts of many laboratories are currently directed towards replacing dead photoreceptor cells with stem cell-derived rods and cones as a strategy to restore vision; however, integrating the new photoreceptors into the retina circuit has been a challenge. The new study suggests that α2δ4 may be the secret ingredient for getting these new cells to properly wire into the neural circuit.
The study was supported by the National Institutes of Health (grants EY018139, EY017606 and EY000331) and an Unrestricted Grant from Research to Prevent Blindness to the Stein Eye Institute, University of California, Los Angeles.