Investigating the disease connection

NIH research into Gaucher disease uncovers a molecule that could also treat Parkinson’s

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BETHESDA, Md.—Gaucher disease is the result of mutations in GBA1, the gene that codes for the protein glucocerebrosidase, which normally works to dispose of certain fats or lipids from cells. As Gaucher disease is a recessive disorder, individuals must have two mutated copies of GBA1 to have the disease. When that’s the case and glucocerebrosidase can’t function as it should, lipids accumulate and can result in enlargement of the spleen, frequent bleeding and bruising, weakened bones and, in the worst cases, neurological disease. An estimated one in 50,000 to one in 100,000 people suffer from Gaucher disease, with individuals of Eastern and Central European (Ashkenazi) Jewish heritage more likely to be at risk.
However, even individuals who present with one mutated copy of GBA1 face consequences—a mutated copy of the gene puts people at a higher risk of developing Parkinson’s disease.
Dr. Ellen Sidransky, a senior investigator with the National Institutes of Health’s National Human Genome Research Institute (NHGRI), tells DDNews that current estimates are that mutations in the Gaucher gene increase an individual’s chances of developing Parkinson’s disease by between five and 10 times. That being said, however, “that would still mean that probably 90 percent of people with Gaucher disease don’t come down with Parkinson’s disease.”
“Gaucher disease is a recessive disorder, so to have Gaucher disease you have to have mutations in both copies of the Gaucher gene, but if you only have mutations in one copy, you still are at an increased risk for Parkinson’s disease,” she explains. “And we now know that if you look at patients with Parkinson’s disease, somewhere between 4 and 10 percent have mutations in the Gaucher gene, which means that it’s the most common known risk factor for Parkinson’s disease.”
Sidransky and her colleagues at the National Institute of Neurological Disorders and Stroke (NINDS) and the National Center for Advancing Translational Sciences (NCATS), recently published the results of new research into Gaucher disease—namely, the nature of the connection with Parkinson’s disease and a molecule that might have the potential to treat both conditions. Sidransky, who has researched Gaucher disease for 28 years, made the connection between the two diseases in 2001.
“This research constitutes a major advance,” commented Dr. Daniel Kastner, NHGRI scientific director and director of the institute’s Division of Intramural Research. “It demonstrates how insights from a rare disorder such as Gaucher disease can have direct relevance to the treatment of common disorders like Parkinson’s disease.”
Dr. Elma Aflaki, a research fellow in Sidransky’s lab, used skin cells of Gaucher patients with and without Parkinson’s disease to generate stem cells in the lab, which were then converted into neurons with features identical to those in people with Gaucher disease. This approach revealed that neurons from individuals with both Gaucher disease and Parkinson’s disease presented with elevated levels of alpha-synuclein, the protein that builds up in the brain in Parkinson’s disease and damages the neurons that control autonomous movement.
Armed with this knowledge, the team used high-throughput drug screening to identify a molecule that could break down cellular waste in patients with mutant GBA1. Drs. Juan Marugan, Samarjit Patnaik, Noel Southall and Wei Zheng, researchers at NCATS Chemical Genomics Center, used the Tox21 robot and found NCGC607 together with researchers from the University of Kansas, Lawrence. The molecule “chaperones” mutant GBA1 so that it can still function, and in stem cell-derived neurons of Gaucher patients, it reversed lipid accumulation and lowered alpha-synuclein levels.
As for what kind of connection there is between lipid accumulation and alpha-synuclein, Sidransky admits that’s “one of the big challenges” for this research.
“What we do know is that alpha-synuclein, which is a protein that aggregates in Parkinson’s disease, seems to play a role—there’s an inverse relationship between the amount of glucocerebrosidase, the enzyme deficient in Gaucher disease, and the amount of alpha-synuclein that you have. So if you have less glucocerebrosidase, because you have a mutation, you tend to have higher levels of alpha-synuclein. And probably more importantly, the other way around, patients with Parkinson’s disease have lower levels of the Gaucher enzyme in their brain.”
While there are some treatment options at present for individuals with Gaucher disease, Sidransky notes that they are just that: treatments, not cures. One, first developed by the NIH roughly 25 years ago, is an enzyme replacement therapy given as intravenous infusions every two weeks. While it improves symptoms in patients with the more common forms of the disease—the ones where the central nervous system isn’t affected—and is effective at shrinking organ size, it is inconvenient and expensive, she says. A more recent therapeutic approach is to inhibit the enzyme that makes the lipid that builds up, which is known as substrate reduction therapy. The issue is there are no treatments for the forms of the disease that affect the central nervous system; “none of the available treatments get into the brain,” Sidransky explains.
She says the team has “many steps ahead” to develop NCGC607 into a drug for Gaucher disease or Parkinson’s disease, such as improving the molecule and further testing. But they will also be doing more work with the neuronal models of Gaucher disease they made for further study.
“We have lots of ideas of what we can use these neurons for,” Sidransky tells DDNews. “This time we made dopaminergic neurons, and we plan to go on and make other kinds of neurons to study in the lab.”

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