RICE (US) — A drug commonly used to treat high-blood pressure may be effective in helping people with an incurable, neuropathic form of Gaucher disease, an inherited metabolic disorder.
Gaucher’s disease, affecting between 1 in 50,000 and 1 in 100,000 people, is characterized by accumulations of a fatty substance in cells and certain organs that can prevent them from functioning properly.
The research, published online in the journal Chemistry and Biology, focuses on the misfolding of proteins, workhorses in the body that determine what cells and organs do and how they do it. Proteins start as chains of amino acids that snap in an instant into distinct configurations, a process that remains one of biology’s great mysteries.
Proteins often misfold even in the healthiest persons, says Laura Segatori, assistant professor of chemical and biomolecular engineering at Rice University and the study’s author. Cells have an elegant, efficient system for eliminating misfolded proteins and other refuse. But the system can at times break down.
In Gaucher disease, proteins containing destabilizing mutations misfold and are degraded very quickly. Loss of these proteins, which normally traffic to the lysosome and catalyze the degradation of lipids, results in buildup of these lipids that can lead to a variety of problems including a malfunctioning liver, enlarged spleen, skeletal disorders, anemia, and neurological disorders.
Segatori and colleagues worked with fibroblasts taken from skin lesions of people with Gaucher and found that lacidipine enhances the protein-folding mechanism by modulating calcium levels and regulating the movement of signaling calcium ions.
Impairment of calcium homeostasis further compromises the folding of already destabilized, mutated versions of the enzyme glucocerebrosidase (GC). Slowing the folding process ever so slightly by regulating calcium stabilizes GC and lets it fold properly and enter the lysosome, where it breaks down lipids.
“If you can force the folding to occur, you can rescue native folding of mutant proteins, which has been shown to lead to restored activity,” Segatori says.
The work may open the door to possible treatments for neuropathic diseases that will be easier on patients and less expensive than enzyme replacement therapy, which involves injecting recombinant protein.
The drug in the study, lacidipine, is a calcium channel blocker also known by the brand names Lacipil and Motens and has three distinct advantages, Segatori says. It’s nontoxic to cells, is a small molecule that readily crosses the blood/brain barrier, and is already approved for use in humans by the Food and Drug Administration.
On the other hand, its effects on neurons has yet to be studied. “We don’t want to say we can cure this disease with calcium blockers, but they are a good tool for research,” Segatori says.
“Essentially, we treat cells with this molecule and see if we rescued the protein activity. If we did, we can then work to understand what the molecule actually did to the folding machinery of the cell.”
Another caution: Calcium blockers might have side effects, Seatori says.
“Their response in the cell is quite broad. That’s why I’m hesitant to say that this could be a cure for Gaucher disease. Maybe we’re rescuing the folding of that enzyme, but we don’t know what else we might be doing.” But the positive implications go beyond Gaucher.
“There is possibly an avenue to use calcium blockers to further the study and treatment of other types of misfolding diseases,” Segatori says. “Similar studies have been conducted using calcium blockers in neurons of Parkinson’s patients.
“The results are highly promising. And there’s also a lot of interest in the correlation between Parkinson’s and Gaucher diseases, because it seems like a lot of people who have Gaucher are at risk for Parkinson’s disease.”
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