Antiparasitic Drug Shows Power Against Alzheimer’s and Dementia
Scientists at UC San Diego and the University of Pittsburgh discover pyrvinium pamoate's potential to rejuvenate cellular structures in neurons
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Researchers at University of California San Diego and the University of Pittsburgh have found that using an existing drug to target nuclear speckles — structures within cell nuclei that regulate proper protein production, folding and degradation — could offer a completely new approach for treating neurodegenerative diseases, such as Alzheimer’s and Parkinson’s. The findings, published in Nature Communications, could also have implications for other diseases involving misfolded proteins, such as prion diseases and retinitis pigmentosa.
While researchers from Pitt led the effort to identify the drug — an existing pinworm treatment called pyrvinium pamoate — and demonstrated its initial potential for targeting nuclear speckles in a petri dish, UC San Diego researchers helped test it in living models of neurodegenerative diseases. Xu Chen, Ph.D., associate professor in the Department of Neurosciences at UC San Diego School of Medicine, was instrumental to this effort.
“These are some of the most promising results I’ve seen in my whole career,” said Chen, whose research focuses on tauopathies, diseases driven by the buildup of tau protein in the brain. These diseases include Alzheimer’s and frontotemporal dementia.
"Tauopathies are devastating diseases, and we are in desperate need of new treatments. This is a tremendous step in the right direction.”
Promising Disease Model Results
By testing pyrvinium pamoate in mouse neurons expressing human tau protein, the team found that the drug reduced the pathological protein level by about 70%.
The researchers also found that human neurons carrying a frontotemporal dementia-associated tau mutation had abnormally shaped nuclear speckles and elevated tau levels. These experiments, led by first author Yuren Tao, a graduate student in Xu Chen’s lab, showed that low doses of the drug restored nuclear speckle shape and dramatically reduced tau levels without causing cellular stress or toxicity.
“These are some of the most promising results I’ve seen in my whole career. Tauopathies are devastating diseases, and we are in desperate need of new treatments. This is a tremendous step in the right direction.”
The drug also showed potential against other diseases in the lab. In experiments led by Yuanyuan Chen, Ph.D., assistant professor of ophthalmology at Pitt, the researchers used mouse retinas cultured in a dish to show that the drug held promise for treating retinitis pigmentosa, a disease in which a key protein in the eye’s rod cells is misfolded, leading to progressive vision loss.
“Our research is painting a picture where dysregulation of nuclear speckles is important for neuron degeneration in the context of many diseases,” said senior author Bokai Zhu, Ph.D., assistant professor in Pitt’s Department of Medicine and the Aging Institute. “The concept of rejuvenating nuclear speckles to treat these diseases is completely novel, but I believe it’s the next frontier of neurodegenerative research.”
Unique Mechanism of Action
To understand how the drug works, Bennett Van Houten, Ph.D., professor in the Pitt Department of Pharmacology & Chemical Biology, led experiments with optical tweezers, which use lasers to precisely manipulate microscopic structures. Nuclear speckles were typically difficult to stretch because of high surface tension, but adding the drug dramatically lowered surface tension, making speckles easy to stretch and rupture.
According to Zhu, when nuclear speckles have lower surface tension, they become less round and spread out to make better contact with chromosomes, leading to greater production of genes regulating proteostasis.
“This was the killer experiment,” said Zhu. “Unlike most drugs, which target a specific receptor, pyrvinium pamoate acts by changing the surface tension of nuclear speckles. This is a totally new idea. Because nuclear speckles act globally on chromosomes, the drug can potentially alter the expression of hundreds of genes — which may be why it is so effective.”
The researchers now hope to move this research into clinical trials to test whether pyrvinium pamoate could effectively treat proteinopathies in humans.
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Additional co-authors on the study include: Shanshan Zhao and Yuhang Ni at UC San Diego School of Medicine and Maci Chambers, Riley K. Arbuckle, Michelle Sun, Syeda Kubra, Matthew A. Schaich, Megan Ye, Imran Jamal, Mads B. Larsen, Daniel Camarco, Eleanor Ickes, Haokun H. Wang, C. DuPont, Bingjie Wang, Silvia Liu, Shaohua Pi and Bill B. Chen from Pitt and University of Pittsburgh Medical Center.
This study was funded, in part, by the National Institutes of Health (grants T32 HL082610, F31 AG080998, 1R35HL139860, R01 EY030991, R01AG074273, R01AG078185, 1DP2GM140924, 1R21AG071893, 1R35GM157978, S10OD028483, R35ES031638, F32ES034982, S10OD032158), the Pittsburgh Liver Research Center through NIH grant P30DK120531 and the Ophthalmology and Visual Sciences Research Center through grant P30 EY08098.
Disclosures: Bill B. Chen is cofounder of Koutif Therapeutic Inc., cofounder and VP of drug discovery for Generian Pharmaceuticals, and co-founder and C.S.O. of Coloma Therapeutics Inc.
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