The National Eye Institute reports that about 11 million older adults in the U.S. suffer from a condition that leads to progressive blindness—known as age-related macular degeneration.
University of Maryland School of Medicine (UMSOM) researchers say they are beginning to understand what goes wrong in the disease in order to develop new therapies to treat it. Using human tissue and mice in a new study (“CIB2 regulates mTORC1 signaling and is essential for autophagy and visual function”) in Nature Communications, they showed that the process which removes the eye’s old, damaged light sensors is disrupted in macular degeneration.
Although more than 50 genes have been linked to the condition, the precise mechanism behind it is unknown. Most people have a form of the condition, for which there are no known effective treatments.
Previously, the senior author of the new study, Zubair M. Ahmed, PhD, professor of otorhinolaryngology-head & neck surgery and ophthalmology at the UMSOM, found out that many families with hearing disorders had genetic mutations in the gene for the CIB2 protein. In work published in 2012 in Nature Genetics, Ahmed also showed that CIB2 was needed for vision in a large human family, as well as in zebrafish.
Further dissecting cell mechanisms behind retinal degeneration
Now, in this latest study, his team built on that previous work to dissect the intricate cell mechanisms behind retinal degeneration.
“Age-related macular degeneration (AMD) is a multifactorial neurodegenerative disorder. Although molecular mechanisms remain elusive, deficits in autophagy have been associated with AMD. Here we show that deficiency of calcium and integrin binding protein 2 (CIB2) in mice, leads to age-related pathologies, including sub-retinal pigment epithelium (RPE) deposits, marked accumulation of drusen markers APOE, C3, Aβ, and esterified cholesterol, and impaired visual function, which can be rescued using exogenous retinoids,” write the investigators.
“Cib2 mutant mice exhibit reduced lysosomal capacity and autophagic clearance, and increased mTORC1 signaling—a negative regulator of autophagy. We observe concordant molecular deficits in dry-AMD RPE/choroid post-mortem human tissues. Mechanistically, CIB2 negatively regulates mTORC1 by preferentially binding to ‘nucleotide empty’ or inactive GDP-loaded Rheb. Upregulated mTORC1 signaling has been implicated in lymphangioleiomyomatosis (LAM) cancer. Over-expressing CIB2 in LAM patient-derived fibroblasts downregulates hyperactive mTORC1 signaling.
“Thus, our findings have significant implications for treatment of AMD and other mTORC1 hyperactivity-associated disorders”.
The team compared healthy mouse eyes to those from a mouse engineered without the CIB2 protein. The researchers observed that the CIB2 mutant mice were not getting rid of their old light sensor proteins (photoreceptors) like healthy mouse eyes did.
“Photoreceptors continue growing in tiny columns in the eye, but over time, light damages the photoreceptors. To combat this, support cells in the eye slowly munch on the old, damaged photoreceptors keeping the columns the correct length,” says first author Saumil Sethna, PhD, instructor of otorhinolaryngology-head & neck surgery.
“If the photoreceptors are not removed or if the process is backed up due to slow digestion by the support cells, like in the CIB2 mutant mice, the undigested material builds up over time, which may contribute to blindness.”
Next, the researchers identified several components in this photoreceptor recycling process, including a group of proteins collectively called mTORC1, which is involved in many human diseases, including cancer, obesity, and epilepsy.
As mTORC1 plays a central decision-maker role for many cellular functions including cleaning up cellular debris, the researchers looked at mTORC1’s activity in the CIB2 mutant mice and saw that mTORC1 was overactive. They confirmed that mTORC1 was also overactive in human eye tissue samples from people with a form of age-related macular degeneration.
By linking the results of the mouse studies to human disease, the researchers say their findings indicate that drugs against mTORC1 may be effective treatments for the most common type of age-related macular degeneration.
mTOR, the core component can be found in two flavors each with different functions, known as complex 1 (as in mTORC1) or complex 2 (mTORC2).
“Researchers have tested many small molecules directed at mTORC1 to treat various diseases, but the problem is that mTOR is needed for so many other cell functions that there are major side-effects when you tinker with it,” says Ahmed. “In our study, we found a backdoor way to regulate mTORC1 (and not mTORC2), which may bypass many of the unpleasant side-effects that normally occur with suppressing mTORC1. We think we may be able to use our new knowledge of this mechanism to develop treatments for age-related macular degeneration and other diseases as well.”
