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Troubled proteins in need of rescue may someday have a champion in a common
drug used to treat high blood pressure.
The Rice Univ. laboratory of bioengineer Laura Segatori reported that
research involving lacidipine, a calcium channel blocker also known by brand
names Lacipil and Motens, could be a key to helping people who suffer from an
incurable, neuropathic form of Gaucher disease. This inherited metabolic
disorder is characterized by accumulations of a fatty substance in cells and
certain organs that can prevent them from functioning properly.
The paper by Segatori, Rice’s T.N. Law Assistant Professor in Chemical and
Biomolecular Engineering, and graduate student Fan Wang and Rice senior Ann
Chou appears in Chemistry
and Biology.
Segatori’s research focuses on the misfolding of proteins. 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 but one that Segatori and
her peers are figuring out, bit by bit.
Proteins often misfold even in the healthiest persons, Segatori said, and
cells have an elegant, efficient system for eliminating misfolded proteins and
other refuse. But the system can 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; this can lead to such problems as a malfunctioning liver,
enlarged spleen, skeletal disorders, anemia, and neurological disorders.
The Rice researchers worked with fibroblasts taken from skin lesions of
people with Gaucher. They found that lacidipine enhances the protein-folding
mechanism by modulating calcium levels and regulating the movement of signaling
calcium ions.
Segatori said 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 said.
Segatori and Wang hope their work opens 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.
Segatori said lacidipine has three distinct advantages: It is nontoxic to
cells, is a small molecule that readily crosses the blood/brain barrier and is
approved for use in humans by the Food and Drug Administration.
On the other hand, the researchers have not yet studied the effect of
lacidipine on neurons. “We don’t want to say we can cure this disease with
calcium blockers, but they are a good tool for research,” Segatori said.
“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.”
She also cautioned that calcium blockers might have side effects.
“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 said. “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.”
Filed Under: Drug Discovery
