This research was supported by BrightFocus
After years spent researching a protein linked to inherited forms of glaucoma, Raquel Lieberman, PhD, and her team at Georgia Tech have provided a three-dimensional view of that protein and a better understanding of what can happen when it becomes misshapen through genetic miscoding.
"Now that we have the 3D visual picture, we can map the mutations and understand why they can be bad for the protein," said Lieberman, an associate professor of chemistry and biochemistry at the Georgia Institute of Technology, and a 2008-11 BrightFocus grantee.
Myocilin is a protein common to parts of the eye and other neural tissues. Genetic mutations cause it to become misshapen through a process known as “protein misfolding.” That, in turn, triggers production of fibrous amyloid residue that clog the drainage channels of the eye.
One of the most frequent contributors to open-angle glaucoma is a chronic rise in intraocular pressure/ That occurs when fluid is unable to circulate freely through the eye's primary drainage channel, a spongy tissue known as the trabecular meshwork (TM). The fluid back-up causes IOP to rise, which in turn damages the sensitive fibers of the optic nerve, causing vision loss.
Previous research by Leiberman et al demonstrated that mutant myocilin is highly resistant to degradation, thus clogging the protein quality control pathway and subverting efficient removal.
"The amyloid-containing myocilin deposits we discovered kill cells that maintain the integrity of TM," Lieberman explained in a 2012 interview. "In addition to debris from dead cells, the fibrils themselves may also form an obstruction in the TM tissue. Together, these mechanisms may hasten the increase of intraocular pressure that impairs vision."
Following initial support from BrightFocus Foundation, Lieberman's project was funded by the National Institutes of Health. She presented her research at the 2014 meeting of the International Society of Eye Research, and this latest accomplishment was featured as the cover story in the April 15 issue of the journal Human Molecular Genetics.
In Protein Misfolding, A Link Between Diseases of Mind and Sight?
Myocilin belongs to a family of olfactomedin domain-containing proteins numbering at least 13 in mammals, the first of which was discovered almost 20 years ago. Half of all OLF domain-containing proteins are expressed in neural tissue. They appear to play roles in fundamental cellular processes and have been implicated in not just glaucoma, but also cancers, inflammatory bowel disorder, attention deficit disorder and childhood obesity.
Nearly 100 different mutations in the 230 amino acid OLF domain of myocilin are linked to glaucoma. In most protein domains of this size, mutating one amino acid won't cause toxic misfolding; the cell will be able to remove the protein efficiently before it causes a problem. But Lieberman et al have shown it’s not easy for the eye to get rid of mutant forms of myocilin.
"Mutating any one of these 100 or so amino acids causes the protein to aggregate," Lieberman said. "Myocilin is exquisitely sensitive to aggregation and the cell cannot handle it."
Genetic defects of myocilin account for approximately 8 to 36 percent of hereditary juvenile-onset glaucoma and 5 to 10 percent of adult-onset hereditary glaucoma.
Based on these findings, new research may look for drugs that prevent or stop myocilin amyloid formation or destroy existing fibrils in glaucoma patients. "These are really the first potential drug targets for glaucoma," said Lieberman in an interview last year. Most current glaucoma medications indirectly treat the symptoms of glaucoma, but not the cause.
As a biochemist, Lieberman studies the “structure-function” relationship between molecules and their physical effects. In that capacity, she also is studying the tendency of misfolded proteins to aggregate and contribute to neurodegenerative disorders like Alzheimer disease.
"In Alzheimer's disease, the deposits are extracellular and kill neurons. In glaucoma the aggregates are not directly killing neurons in the retina to cause vision loss, but they are cytotoxic in the pressure-regulating region of the eye. It's parallel to all these other amyloids that are out there in neurodegenerative disease,” Lieberman said last year.
BrightFocus grantee Raquel Lieberman and researchers at Georgia Tech have created a 3D depiction of myocilin, a protein implicated in hereditary forms of glaucoma (above). Mutated forms of myocilin are a new drug target. Thus, the work of Lieberman et al to “map” the myocilin molecule will make it possible to design drugs that bind to it more effectively. The images below depict the extreme shape differences between normal myocilin, which forms in straight fibrils common to many amyloids, and disease-causing variants that form large circular fibrils.
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