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Thursday, November 30, 2023

Academics & Research

Researchers battle Parkinson’s disease using mouse model

Parkinson’s disease may prove to be no match for a team of UH researchers at the Center of Nuclear Receptors and Cell Signaling.

CNRCS Director Jan-Åke Gustafsson and professor Margaret Warner, along with their team of researchers, have found a link between beta-sitosterol — present in many plants and good for preventing cholesterol absorption from one’s diet — and ALS-Parkinson’s disease. This discovery may aid in the fight against Parkinson’s and was recently published in Proceedings of the National Academy of Sciences.

Parkinson’s disease is a chronic progressive neurological disease linked to a decrease in dopamine, production in the substantia nigra and marked by tremors in resting muscles, rigidity, slowness of movement, impaired balance and a shuffling gait.

“If ALS-Parkinson’s patients do have a defect in LXRbeta signaling, they will benefit from pharmaceuticals which target signaling of this receptor. Many such drugs are being developed at present,” Warner said.

Authors Yubing Dai and Wanfu Wu researching in the CNRCS lab. | Amanda Hilow/The Daily Cougar

Authors Yubing Dai and Wanfu Wu researching in the CNRCS lab. | Amanda Hilow/The Daily Cougar

Gustafsson has had a long-standing interest in nuclear receptors because they are activated by the small molecules like hormones, and medication can be developed to increase or decrease their activity. In 1995, Gustafsson’s lab discovered two novel nuclear receptors — one was LXRbeta. An efficient way to unmask the function of the newly discovered genes is to use gene technology to eliminate the hormone in mice and see what happens.

“The receptor continues to show promise as a potential therapeutic target for this disease, as well as other neurological disorders,” Gustafsson said in a press release for “LXRbeta performs an important function in the development of the central nervous system, and our work indicates that the presence of LXRbeta promotes the survival of dopaminergic neurons, which are the main source of dopamine in the central nervous system.”

During World War II, ALS-Parkinson’s disease was prevalent in the Pacific Islands and Guam where there was a shortage of wheat. During that time, people had to make bread from cycad seeds, which contain a high level of beta-sitosterol.

“The reason for the susceptibility of certain people in Guam to toxicity from beta-sitosterol remained a mystery until we developed the LXRbeta knockout mice,” Warner said. “These mice develop ALS-Parkinson’s disease spontaneously as they age, and the disease is made worse if beta-sitosterol is added to their diet.”

However, it was discovered that LXRbeta knockout mice did not need to be fed beta-sitosterol to develop Parkinson’s disease. Meaning UH researchers have to look for the possibility that people develop ALS- Parkinson’s disease because of defective LXRbeta signaling.

LXRbeta is a ligand-activated nuclear receptor and one of its ligands is beta-sitosterol. This led UH researchers to conclude that an intact LXRbeta is essential to prevent development of Parkinson’s disease and that people who develop Parkinson’s disease may have a LXRbeta signaling deficiency.

The researchers are hoping that many clinics will begin to look at LXRbeta signaling in human patients to evolve theses finding for the future.

These studies are ongoing at the CNRCS in collaboration with the global authority in ALS, professor Stan Appel at the Methodist Hospital Research Institute.

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