Researchers Discover Form of CF Shares Mechanism with Cystinosis

Rare Daily Staff

The same cellular mechanism involved in a form of cystic fibrosis is also implicated in a form of the rare disease lysosomal storage disease cystinosis, according to researchers at the University of Michigan.

The work has pointed to the potential to repurpose an approved cystic fibrosis drug to benefit people with cystinosis.

The problem begins when the lysosome, an organelle within the cell, is unable to do its job. Often called the recycling center of the cell, the lysosome takes in cellular garbage, breaks it down into reusable cellular building blocks, then transports those materials back into the cell.

But when the protein that transports one of the recycled amino acids back into the cell mutates and fails, a cellular mechanism cleans up the faulty protein, allowing amino acid, or cystine, to build up in the lysosome.

In cystinosis, this causes cystine crystals to build up in the cell. This disrupts the cell, and eventually, tissues and ultimately organs, particularly the kidneys and the eyes.

“If cystinosis not treated at an early age, some of the effects are irreversible and it could include impaired growth, kidney failure, and neurological problems,” said Varsha Venkatarangan, graduate student in the U-M Department of Molecular, Cellular and Developmental Biology and lead author of the study. “Typically, the symptoms of the disease are treated rather than the root problem. So, we have been wondering what could be the possible cellular mechanism of this disease.”

Venkatarangan worked with fibroblasts, skin tissue cells derived from patients with the disease. Using these cells, she determined that this disease mechanism called endoplasmic-reticulum-associated degradation, or ERAD, degrades a mutated version of the lysosome cystine transporter.

ERAD is the same mechanism behind other diseases including a major form of cystic fibrosis. And because this mechanism has been identified, the researchers were able to show that previously identified drug molecules were able to help the transporter protein remain stable. Their findings are now published in the Journal of Clinical Investigation.

“This drug molecule is a small chemical that can somehow assist the protein folding of the mutant and protect it from being degraded,” said Ming Li, professor in the University of Michigan Department of Molecular, Cellular and Developmental Biology. “This chemical chaperone helps it achieve the right formation so that it can be functional.”

Because this is a commonly known disease mechanism, involved in cystic fibrosis, drug molecules had already been identified to work around the ERAD mechanism and prolong the life of the protein. These drug molecules, Li said, are called chemical chaperones and help the protein achieve the right formation so that they can be functional.

“This small chemical chaperone can somehow magically—we don’t know the exact mechanism—bind to our mutant and protect the protein from being degraded,” Li said.

The researchers were able to stabilize the protein and determine that it was in the right location where it could function to ferry amino acids out of the lysosome, but they then needed to determine whether the transporter was still functional. Performing an assay in collaboration with UCSD, the researchers measured the cystine concentration in the lysosome. With a functional transporter, the lysosome would have lower amounts of amino acid.

“The reduction was pretty dramatic—nearly a 70 percent reduction of the accumulation level,” Li said. “That directly brought the system level to almost normal. If we actually used this chemical chaperone to treat patients, it’s possible that we could directly bring down the cystine accumulation in the lysosome.”

Photo: Varsha Venkatarangan, graduate student in the U-M Department of Molecular, Cellular and Developmental Biology at the University of Michigan