Prof pursues pill to halt Gaucher

Prof pursues pill to halt Gaucher’s, Parkinson’s, Alzheimer’s
Rice researcher takes part in paper on treatment for protein-folding diseases

Rice News staff

What if a pill could keep the effects of Gaucher’s and similar diseases in check?

That’s the goal of a project at Rice that builds upon basic research by a recent addition to the Department of Chemical and Biomolecular Engineering.


Laura Segatori is working to treat lysosomal storage disorders (LSDs) like Gaucher’s and Tay-Sachs in ways that could also help Parkinson’s and Alzheimer’s sufferers. All are the result of genetic mutations or sporadic conditions that disrupt the way proteins, the body’s basic building blocks, fold within cells. The way a protein folds determines its function.

”Any time there’s a problem with the folding, even little changes with the structure, that means the activity of the protein is compromised,” Segatori said.

She hopes to make treating the diseases easier and less expensive by arresting the process that causes proteins to misfold.

”The idea is to look at these neurodegenerative diseases in a completely different way by enhancing the cells’ quality-control system,” said Segatori, a native of Bologna, Italy, who joined Rice a year ago as the T.N. Law Assistant Professor in Chemical and Biomolecular Engineering. She  and several co-authors published an article on the topic in the Sept. 5 issue of the life sciences journal Cell.

”Right now, the therapy that exists, particularly for Gaucher’s disease, is enzyme replacement, in which the enzyme (aka the protein) is synthesized and injected into the patient,” said Segatori. ”It’s extremely expensive, and you need a lot of injections.”

She said her treatment would not only be cheaper to manufacture, but could also be administered orally.

The key is finding small molecules that can cross the blood-brain barrier, where they would be available to the central nervous system and could cure neuropathic forms of LSDs like Gaucher’s and Tay-Sachs. It’s a cure that does not currently exist.

The Cell article reported on two molecules, proteostasis regulators that promote the proper folding of LSD proteins, despite genetic mutations that would otherwise keep them from doing so. The regulators, which affect the cell’s folding pathway, and not the specific misfolded protein associated with the disease, could be used to treat multiple diseases. When used in concert with disease-specific molecules called pharmacologic chaperones, a cell’s ability to properly fold proteins is greatly enhanced, she said.

”These are all diseases caused by mutations that destabilize the folding,” said Segatori, who worked on the Cell paper while a postdoc at the Scripps Research Institute in San Diego. ”But the mutation doesn’t really compromise the function of the protein.” If medicinal molecules could help them fold correctly, the proteins would then go do their jobs, just like any other.

The regulators described in the paper cannot cross the blood-brain barrier. That makes them unsuitable for treating neuropathic forms of the disease, so finding ”small molecules” that can is the focus of current research by Segatori and her students. ”Small molecules are the treatment of choice for human diseases,” she said, because of their bioavailability (the percentage of a drug that reaches its target), their ability to cross the blood-brain barrier and their cost. ”There are huge collections of these small molecules that can be screened in high-throughput processes to isolate the ones effective for the treatment of the specific disease,” she said.

The molecules would target cells responsible for folding proteins that function in the lysosome as hydrolytic enzymes. ”The lysosome is an organelle that handles the garbage of a cell,” she explained. ”Everything that needs to be destroyed and thrown away goes into the lysosome, where there are enzymes that chop everything up and get rid of it.” But if the enzymes never reach the lysosome, chaos ensues as the garbage accumulates.

”Any time there’s a problem with the folding, even little changes with the structure, that means the activity of the protein is compromised,” Segatori said.

Of the two proteostasis regulators described in the paper, one would help proteins fold properly into the three-dimensional shapes that give them their characteristics. The other would ”downregulate” the degradation of misfolded proteins to give them more time to fold before the cell throws them aside.

Since working on the paper that dealt specifically with Gaucher’s and Tay-Sachs — which she described as loss-of-function diseases, in which proteins are prone to misfolding and rapid degradation — Segatori and her students have turned their attention to what she called ”the other side of the coin.” Gain-of-toxic-function diseases, including Parkinson’s and Alzheimer’s, are caused by the build-up of misshapen proteins that form plaques in the brain. For these diseases, she wants the proteins to degrade faster, not slower, so that cells can eliminate them.

Until not too long ago, people were more focused on how to get rid of those plaques,” she said. “But really, that’s not the problem – that’s the consequence. The problem is upstream.

“If you find a therapeutic strategy that works for Gaucher’s disease, most likely it will work for a lot of other loss-of-function diseases,” said Segatori. “I don’t know if it will be possible to have one pill for multiple diseases, but the same therapeutic approach can be used, as we showed in the Cell paper.”

About Mike Williams

Mike Williams is a senior media relations specialist in Rice University's Office of Public Affairs.