Skip Navigation LinksHome > July 4, 2013 - Volume 13 - Issue 13 > Two Agents Found to Have Anti-Prion Activity — Experts View...
Neurology Today:
doi: 10.1097/01.NT.0000432294.71902.10
Features

Two Agents Found to Have Anti-Prion Activity — Experts View the Screening Method as Promising

Valeo, Tom

Free Access
Article Outline
Back to Top | Article Outline

ARTICLE IN BRIEF

In cell culture, two drugs, tacrolimus and astemizole inhibited replication of two prion strains — RML and 22L — in cell culture, with mixed results: Tacrolimus failed to extend the life of infected mice when administered for 30 days; astemizole prolonged the survival of the RML-infected mice modestly, but apparently by stimulating the cellular mechanism for removing junk from the cell — an effect the authors believe could be used to fight a variety of diseases that involve misfolded proteins, including Alzheimer's, Parkinson's, and Huntington's disease.

Prion diseases begin when normal prion protein (PrP) misfolds into a highly toxic shape. The misfolded PrP then aggregates and becomes infectious, initiating the misfolding of more normal PrP. Without normal PrP this irreversible chain reaction could never get started, and PrP does not appear to be essential to life. Mice bred without it appear to be normal — and virtually immune to prion infection.

That fact spurred researchers at the Scripps Research Institute in Jupiter, FL, to search for compounds that would decrease cell surface PrP expression and thereby frustrate prion propagation. After developing a new type of high-throughput assay they screened 1,280 Food and Drug Administration (FDA)-approved drugs that might have anti-prion activity and selected two — tacrolimus, an immunosuppressant used on organ transplants, and astemizole, an antihistamine that has been withdrawn from the US and European market, but is still used elsewhere in the world.

They reported in the April 23 issue of the Proceedings of the National Academy of Sciences (PNAS) that both drugs inhibited replication of two prion strains — RML and 22L — in cell culture, with mixed results: Tacrolimus failed to extend the life of infected mice when administered for 30 days; astemizole prolonged the survival of the RML-infected mice modestly, but apparently by stimulating autophagy — the cellular mechanism for removing junk from the cell — an effect the authors believe could be used to fight a variety of diseases that involve misfolded proteins, including Alzheimer's, Parkinson's, and Huntington's disease.

“We first thought that tacrolimus might be involved in autophagy because of one of its cellular binding partners,” said lead author Corinne Ida Lasmézas, DVM, PhD, professor in the department of infectology at Scripps. “The surprise was that tacrolimus didn't stimulate autophagy, but astemizole did.”

Despite this surprising result, the authors contend that reducing cell surface expression of PrP may provide an effective weapon against other diseases, including Alzheimer's disease, which display prion-like activity. (See “Researchers Tackle Prion Activity in Alzheimer's Disease.”)

Back to Top | Article Outline

EXPERTS COMMENT

The Scripps researchers seem to have hit on a promising strategy, said Sina Ghaemmaghami, PhD, assistant professor of biology at the University of Rochester, who has also been using high-throughput assays to screen for small anti-prion compounds. “We actually identified one compound that seems to work by a similar mechanism (as tacrolimus), which is to reduce the expression level of cellular prion protein,” he said.

Dr. Ghaemmaghami believes the assay developed by the Scripps researchers, which can screen up to 100,000 compounds a day, will be a great asset. “Although they screened only about 1,000 compounds, I can see how their screening strategy can be adapted to crank through hundreds of thousands of compounds, which would be a very rapid way of identifying promising leads,” he said.

Claudio Soto, PhD, professor of neurology at the University of Texas Health Science Center at Houston, agreed. “They can screen libraries of approved drugs,” he said. “That makes a lot of sense. In a disease like this you don't want to do full clinical trial testing for safety and all that because there is no company that would be interested in investing. It makes sense to look at existing drugs.”

Dr. Soto does not see much promise in the idea of reducing normal prion protein, however, because there's no way to know who needs treatment for prion disease until it's too late. “It will be very difficult to produce a benefit by eliminating abnormal proteins,” he said. “By that point the brain is already largely destroyed. Treatment has to begin before that, but there is no way to know which patients are developing the disease. For prion diseases we need to do something before protein accumulates. We need things that prevent damage to brain, or find ways to recover lost functionality — perhaps stem cell technology to replace lost neurons.”

Michael D. Geschwind, MD, PhD, associate professor of neurology and Michael J. Homer chair in neurology at the University of California, San Francisco, agreed with other experts that the screening method the researchers developed shows great promise. “Anything you can do with high-throughput screening makes things much easier,” he said. “Also, it's nice to have a screening method where you don't need infectious prions.”



Image Tools


Image Tools

However, Dr. Geschwind, who also has been seeking a better understanding of rapidly progressive dementias including prion diseases, said he was otherwise underwhelmed by the results reported in the PNAS paper. “They used one mouse model, and they didn't use humanized mice,” he said, emphasizing that human prions are distinctly different. “So the fact they showed an effect in only one mouse model is troublesome. If they had showed an effect in multiple animal models, and a humanized mouse model, that would have been more impressive.”

Also, he considers the increase in survival time barely significant. “If you took two random groups of mice and showed survival after infecting them with prions, you might see the same difference in survival even without treatment. I'm not convinced by this data that the treatment had any meaningful effect in mice, and it's only in one mouse model, and it's not a humanized mouse model.”

Back to Top | Article Outline

RESEARCHERS TACKLE PRION ACTIVITY IN ALZHEIMER'S DISEASE

“All neurodegenerative diseases have a prion-like component,” said George S. Bloom, PhD, who was not involved with the studies but has done similar research. Dr. Bloom, professor of biology and cell biology at the University of Virginia, was the lead author of a recent paper in Prion that described the prion-like properties of both amyloid-beta and tau, which misfold in Alzheimer's disease.

“All the major ‘bad’ proteins in neurodegenerative diseases — tau and amyloid-beta in Alzheimer's, huntingtin in Huntington's disease, alpha-synuclein in Parkinson's disease — have prion-like properties in the sense that misfolded proteins transfer their misfolding to normal proteins. That explains, in part, how disease is spread through brain,” said Dr. Bloom.

“Astemizole seems to stimulate autophagy, and that may be applicable to some or all of the neurodegenerative diseases as well as to prion diseases,” he said. “Tacrolimus dramatically lowers cell surface levels of prion protein but does not stimulate autophagy, and does not protect mice. That says that simply lowering prion protein levels is not sufficient for protecting against prion diseases. Maybe we shouldn't worry about normal prion protein.”

Several other labs are investigating the role of prion activity in Alzheimer' disease (AD). Work done in the lab of Stephen Strittmatter, MD, PhD, at the Yale University School of Medicine, has shown that amyloid-beta (Abeta) oligomers act via normal prion protein (PrP) to initiate Alzheimer's symptoms. “For example, genetic deletion of PrP, or a blockade with anti-PrP antibodies, relieves memory deficits in mice with human familial Alzheimer transgenes, and prevents the ability of Abeta oligomers to impair synaptic plasticity,” Dr. Strittmatter said. “We are working to develop AD therapies based on PrP as a target. I believe this might include a small molecule PrP blockade, anti-PrP antibodies, and PrP-lowering agents.”

A recent paper in the Journal of Biological Chemistry reports that prion protein binds with high affinity to Abeta oligomers. N1, an N-terminal fragment of PrP, appears to be sufficient for such binding, and prevents the oligomers from becoming toxic in cells, worms, and mice. The authors speculate that N1 blocks the interaction of a specific Abeta oligomer with cellular receptors responsible for toxicity — receptors that may include PrP. Therefore, they conclude, compounds derived from N1 might possess the ability to block the neurotoxic effects of Abeta and other aggregated proteins linked to neurodegenerative diseases.

Another recent paper in the Journal of Biological Chemistry reports that Abeta and PrP can enter a pathological downward spiral in which cholesterol-rich lipid rafts promote the production of toxic Abeta, which then attaches to PrP receptors and disrupts BACE1 inhibition, normally mediated by PrP. This results in an increase in the production of toxic Abeta.

—Tom Valeo

Back to Top | Article Outline

LINK UP FOR MORE INFORMATION:

•. Karapetyan YE, Sferrazza GF, Lasmézas CI, et al. Unique drug screening approach for prion diseases identifies tacrolimus and astemizole as antiprion agents. Proc Natl Acad Sci. U S A. 2013; 110:(17):7044–7049. E-pub 2013 Apr 1.

•. Nussbaum JM, Seward ME, Bloom GS. Alzheimer disease: a tale of two prions. Prion. 2013; 7:(1):14–9.

•. Fluharty BR, Biasini E, Harris DA, et al. An N-terminal fragment of the prion protein binds to amyloid-β oligomers and inhibits their neurotoxicity in vivo. J Biol Chem. 2013; 288:(11):7857–66.

•. Rushworth JV, Griffiths HH, Hooper NM, et al. Prion protein-mediated toxicity of amyloid-β oligomers requires lipid rafts and the transmembrane LRP1. J Biol Chem. 2013; 288:(13):8935–51.

•. Neurology Todayarchive on prions: http://bit.ly/11g3fSd.

Wolters Kluwer Health | Lippincott Williams & Wilkins

Article Tools

Images

Share