Journal News

Peering into ocular waste recycling

Researchers uncover a mechanism that causes blindness, could lead to targeted therapies
Marissa Locke Rottinghaus
April 4, 2023

A recent study in the Journal of Biological Chemistry revealed the key to a protein that commonly causes blindness. The biological process involves a protein that is essential for transporting toxic compounds out of the eye, similar to a garbage recycling service. The challenge is that, like food and the waste it generates, these compounds are essential for the eye to function properly — until they build up and cause blindness.

Diagram of the parts of the eye.

The scientists behind the study research a protein transporter, called ABCA4, that lines the edges of specialized photoreceptor cells in the retina and is normally poised to remove toxic, fatty retinal byproducts called N-Ret-PE. Retinal is a derivative of vitamin A, which is found in foods such as leafy green vegetables.

“Retinal is critical for vision,” said Robert Molday, a professor of biochemistry and molecular biology at the University of British Columbia who oversaw the work. “But, it's also potentially very toxic because it has a very reactive element. So, cells have to be able to balance between using retinal for sustained vision as well as managing its toxicity .”

Mutations in ABCA4 can cause N-Ret-PE buildup, which leads to vision loss in diseases such as Stargardt disease. Stargardt disease is the most common inherited form of macular degeneration and affects approximately 30,000 people nationwide. There is currently no therapy or cure for the disease.

Courtesy of Molday et al.
A. Normal vision (top image) and loss in central vision experienced by an individual with Stargardt macular degeneration (bottom image).  B. Structure of ABCA4 within the membrane showing the binding of N-Ret-PE (spheres).  Energy from ATP hydrolysis is used to transport N-Ret-PE across the membrane facilitating its removal from rod and cone photoreceptor cells. Mutations in residues in the binding pocket of ABCA4 cause a loss in N-Ret-PE binding and transport resulting in the buildup of N-Ret-PE and a loss in vision.

The researchers were interested in finding out how the ABCA4 transporter malfunctions to cause vision loss. They found that a portion of the protein that interacts with N-Ret-PE, known as the binding pocket, is inert in some patients with Stargardt disease. Therefore, the toxic compounds slip out of the ABCA4 transporter and cannot be removed from the retina.

Next, by changing the makeup of ABCA4, the researchers showed they could mimic the effect of the Stargardt mutations.

“We were able to elucidate the mechanism of binding, which paves the way for treatments for Stargardt disease,” Tongzhou Xu, a postdoctoral fellow at UBC and lead author of the study, said.

The team is optimistic that one day there will be a targeted therapeutic for patients with Stargardt disease that may use gene therapy and specialized particles for delivery to the eye. Gene therapy approaches have already been successfully used to correct mutations in a similar transporter, which causes cystic fibrosis.

“We are now applying two types of technologies to alter ABCA4,” Molday said. “One which was developed to specifically correct the DNA with gene-editing approaches. We are coupling that with lipid nanoparticles, which have been used in the COVID-19 vaccine to encapsulate mRNA. So, by combining these two technologies, we envision being able to potentially correct the defects in individuals with Stargardt's disease that have specific point mutations.”

Enjoy reading ASBMB Today?

Become a member to receive the print edition monthly and the digital edition weekly.

Learn more
Marissa Locke Rottinghaus

Marissa Locke Rottinghaus is the science and policy communications specialist for the ASBMB.

Related articles

From the journals: August 2018
John Arnst, Sasha Mushegian, Angela Hopp & Laurel Oldach
From the journals: JBC
Ken Farabaugh
A second chance for a healthy heart
Marissa Locke Rottinghaus
Finding a way to combat long COVID
Marissa Locke Rottinghaus

Get the latest from ASBMB Today

Enter your email address, and we’ll send you a weekly email with recent articles, interviews and more.

Latest in Science

Science highlights or most popular articles

'CoA as the central core'

'CoA as the central core'

June 2, 2023

ASBMB meeting on CoA and its derivatives will take place in Wisconsin in August and will feature sessions on metabolism, intracellular cross talk, proteostasis, autophagy and technological advances in mass spectrometry.

Study uncovers a unique, efficient method of copper delivery in cells

Study uncovers a unique, efficient method of copper delivery in cells

May 28, 2023

Discovery will help in treating Menkes disease, other copper deficiency disorders.

As microbiome science forges ahead, will some be left behind?

As microbiome science forges ahead, will some be left behind?

May 27, 2023

The FDA’s approval of the first fecal microbiota treatment was a watershed moment — and also a wakeup call.

Cystic fibrosis: current understanding and prospects
Health Observance

Cystic fibrosis: current understanding and prospects

May 26, 2023

In observance of National Cystic Fibrosis Awareness Month, we talked with researcher Neil Bradbury.

A great escape — how SARS-CoV-2 evades our defenses
Journal News

A great escape — how SARS-CoV-2 evades our defenses

May 25, 2023

Preliminary evidence shows that SARS-CoV-2 uses molecular mimicry, in which one of its proteins acts like a protein in our immune system.

John H. Exton: A cell signaling pioneer

John H. Exton: A cell signaling pioneer

May 24, 2023

Colleagues recall a distinguished member of the Vanderbilt University faculty for six decades who had been an ASBMB member since 1970.