Age-related macular degeneration (AMD) is the primary cause of vision loss in Western countries. This condition involves the progressive deterioration of central vision due to the build-up of lipofuscin, a combination of lipids and proteins, within the retina, resulting in cell damage. Despite the absence of effective treatments for AMD, the mechanisms by which healthy eyes prevent the accumulation of lipofuscin remain unclear.
Researchers from Yale University and the University of Tübingen in Germany have made a significant breakthrough in understanding the eye's protective mechanism against age-related macular degeneration (AMD). Their study revealed that melanin, through an unconventional quantum chemistry reaction, plays a role in eliminating lipofuscin. This groundbreaking discovery has the potential to shape future treatments for AMD.
"It's beginning to look like melanin is nature's solution to a variety of biology's challenges," said Douglas E. Brash, professor of therapeutic radiology and dermatology at Yale and co-author of the new study.
The findings were published in the Proceedings of the National Academy of Sciences.
Photoreceptors, specialized cells in the eye, play a crucial role in converting light into signals transmitted to the brain. These cells contain membrane stacks known as discs, housing rhodopsin molecules responsible for capturing light and initiating electrical signals. Through a recycling process, the top discs collect useful material for reuse, while new discs are continually formed at the bottom of the stack. This ongoing cycle persists throughout an individual's lifetime.
During the process of disc turnover, certain materials that are unable to be broken down contribute to the formation of lipofuscin. The accumulation of lipofuscin is detrimental to retinal cells, leading to age-related macular degeneration (AMD).
Earlier studies on albino mice have demonstrated that lipofuscin buildup and retinal damage occur earlier compared to other cases. In the recent study, researchers employed high-magnification electron microscopy to examine undigested discs within retinal cells of both albino mice and pigmented mice genetically modified to simulate AMD.
"The remnants of undigestible discs were ten-fold more frequent in albino mice than in pigmented mice," said Ulrich Schraermeyer, a professor in the Center for Ophthalmology at the University of Tübingen and senior author of the study.
Melanin, a pigment present in hair, skin, and eyes, exhibits variations among individuals and experiences reduced efficacy as aging occurs. In albino mice, the absence of melanin causes their distinctive coloring. Recognizing the potential role of this pigment in impeding lipofuscin accumulation, the research team stimulated melanin synthesis in albino mice. Remarkably, this intervention led to a notable reduction in lipofuscin levels, as observed by the researchers.
Dr. Brash's research focuses on investigating the connection between ultraviolet (UV) light exposure and skin cancer development. In earlier studies, his laboratory unveiled that melanin, through a process known as "chemiexcitation," can trigger a reaction leading to DNA damage.
"These quantum chemistry reactions excite a melanin electron to a high energy state and flip its spin, allowing unusual chemistry afterward," said Brash.
In order to explore the potential role of chemiexcitation in lipofuscin removal, Dr. Brash identified specific compounds capable of directly exciting electrons, bypassing the need for melanin involvement. Additionally, he discovered a compound with the ability to obstruct chemiexcited melanin from initiating subsequent reactions.
"We know that melanin becomes less effective as we get older," Brash said. "So once the Schraermeyer lab had determined that melanin was required for photoreceptor disc turnover and essential for preventing lipofuscin buildup, we wanted to see if a chemiexcited drug might be a way to circumvent melanin while inducing its effects."
The researchers tested the compounds on retinal tissue from albino mice.
"In two days, the lipofuscin diminished substantially," said Yanan Lyu, lead author of the study and a researcher at Shanghai General Hospital in China. "And that improvement was blocked by the excited-state quencher."
The specific chemical process by which the excited electrons reverse lipofuscin is yet to be determined. However, Schraermeyer holds an optimistic outlook on the potential translation of this discovery into clinical applications.
"For 30 years I was convinced that melanosomes—the organelles in cells that create melanin—degrade the lipofuscin but couldn't identify a mechanism," he said. "Chemiexcitation is the missing link, and it should let us bypass the problem that AMD begins when the eye's melanin declines with age. A drug that is chemiexcited directly may be a breakthrough for our patients."
Yanan Lyu et al, Chemiexcitation and melanin in photoreceptor disc turnover and prevention of macular degeneration, Proceedings of the National Academy of Sciences (2023). DOI: 10.1073/pnas.2216935120