Bile Acids Slow Progression of Prion Disease

For much of her adult life Valerie Sim has been fascinated by a disease very few in the world can claim to even begin to understand. Sim is one of Canada’s foremost authorities on prion disease–more commonly known as bovine spongiform encephalopathy, or mad cow disease in cattle, or Creutzfeldt-Jacob disease among humans. In both cases there is no cure; nor are there treatments available. But Sim’s latest research is providing new hope for the future.

Sim, an assistant professor in the University of Alberta’s Faculty of Medicine & Dentistry, and Leonardo Cortez, a research associate in her lab, are the main authors of a study in the August issue of the Journal of Virology examining the use of two bile acids as possible therapeutic treatments for prion disease. The research found that ursodeoxycholic acid (UDCA) and tauroursodeoxycholic acid (TUDCA) helped slow the progression of the disease if given early in the disease process. The bile acids appear to bind the proteins (prions) that cause disease and prevent them from spreading.

“These compounds are normally used to help digest lipids and fats, but interestingly they’ve been used in naturopathic and Chinese remedies for hundreds of years,” says Sim. “Right now we have nothing to offer patients with prion disease. This could be a way forward.”

Image shows immunostaining of variant CJD prion proteins.
Creutzfeldt-Jacob disease is rare in humans, affecting approximately one person out of every million. It is a fatal neurodegenerative disease caused when a protein in the brain takes on a wrong shape, which then converts other proteins to misfold as well. Image is for illustrative purposes only and shows immunostaining of variant CJD prion proteins. Credit: Sbrandner.

Creutzfeldt-Jacob disease is rare in humans, affecting approximately one person out of every million. It is a fatal neurodegenerative disease caused when a protein in the brain takes on a wrong shape, which then converts other proteins to misfold as well. When that occurs, it begins a tremendously accelerated type of dementia, affecting a person’s memory, coordination, vision and balance. While most cases are sporadic and unpredictable, in about 10 per cent of all cases the disease is actually inherited. In extremely rare cases it can also be transmitted through eating contaminated meat.

While Sim’s research marks important new progress, she cautions it needs further study in humans. She also notes that the use of UDCA and TUDCA would not be effective in most cases of prion disease as patients only come to medical attention after the disease is already too far progressed. She does believe the findings could have application for the 10 per cent of Creutzfeldt-Jacob patients who have a genetic form of the disease and who could seek early long-term treatment.

“Some of those people know they are carriers of the disease and currently we have nothing we can give them that works,” says Sim. “This is not a cure, but may have some benefit if given early. And for these patients, any benefit is better than nothing.”

With possible clinical applications still years away, Sim and her team are continuing their research. They hope to learn if UDCA and TUDCA would have long-term health benefits for patients with prion disease, or if it would simply extend life at the end stage of the disease when symptoms are at their worst. They are also testing to see if they can boost the effectiveness of UDCA and TUDCA by combining them with other anti-prion compounds.

While work continues on the research, Sim says there are still common sense solutions that can be taken in the meantime to keep the brain functioning at its best.

“I wouldn’t propose going out and adding bile acids to the water in an attempt to prevent such a rare disease,” she says. “For now, the best ways to reduce the risk of the more common dementias are to stop smoking, exercise, eat well, and get a healthy night’s sleep. These are much better for the brain.”

About this neurology research

Funding: Research funding was provided by Alberta Innovates – Bio Solutions, Alberta Innovates – Health Solutions, and the University Hospital Foundation.

Source: University of Alberta
Image Credit: The image credited to Sbrandner and is licensed GFDL
Original Research: Abstract for “Bile Acids Reduce Prion Conversion, Reduce Neuronal Loss, and Prolong Male Survival in Models of Prion Disease” by Leonardo M. Cortez, Jody Campeau, Grant Norman, Marian Kalayil, Jacques Van der Merwe, Debbie McKenzie, and Valerie L. Sim in Journal of Virology. Published online May 13 2015 doi:10.1128/JVI.01165-15


Abstract

Bile Acids Reduce Prion Conversion, Reduce Neuronal Loss, and Prolong Male Survival in Models of Prion Disease

Prion diseases are fatal neurodegenerative disorders associated with the conversion of cellular prion protein (PrPC) into its aberrant infectious form (PrPSc). There is no treatment available for these diseases. The bile acids tauroursodeoxycholic acid (TUDCA) and ursodeoxycholic acid (UDCA) have been recently shown to be neuroprotective in other protein misfolding disease models, including Parkinson’s, Huntington’s and Alzheimer’s diseases, and also in humans with amyotrophic lateral sclerosis. Here, we studied the therapeutic efficacy of these compounds in prion disease. We demonstrated that TUDCA and UDCA substantially reduced PrP conversion in cell-free aggregation assays, as well as in chronically and acutely infected cell cultures. This effect was mediated through reduction of PrPSc seeding ability, rather than an effect on PrPC. We also demonstrated the ability of TUDCA and UDCA to reduce neuronal loss in prion-infected cerebellar slice cultures. UDCA treatment reduced astrocytosis and prolonged survival in RML prion-infected mice. Interestingly, these effects were limited to the males, implying a gender-specific difference in drug metabolism. Beyond effects on PrPSc, we found that levels of phosphorylated eIF2α were increased at early time points, with correlated reductions in postsynaptic density protein 95. As demonstrated for other neurodegenerative diseases, we now show that TUDCA and UDCA may have a therapeutic role in prion diseases, with effects on both prion conversion and neuroprotection. Our findings, together with the fact that these natural compounds are orally bioavailable, permeable to the blood-brain barrier, and U.S. Food and Drug Administration-approved for use in humans, make these compounds promising alternatives for the treatment of prion diseases.

IMPORTANCE Prion diseases are fatal neurodegenerative diseases that are transmissible to humans and other mammals. There are no disease-modifying therapies available, despite decades of research. Treatment targets have included inhibition of protein accumulation, clearance of toxic aggregates, and prevention of downstream neurodegeneration. No one target may be sufficient; rather, compounds which have a multimodal mechanism, acting on different targets, would be ideal. TUDCA and UDCA are bile acids that may fulfill this dual role. Previous studies have demonstrated their neuroprotective effects in several neurodegenerative disease models, and we now demonstrate that this effect occurs in prion disease, with an added mechanistic target of upstream prion seeding. Importantly, these are natural compounds which are orally bioavailable, permeable to the blood-brain barrier, and U.S. Food and Drug Administration-approved for use in humans with primary biliary cirrhosis. They have recently been proven efficacious in human amyotrophic lateral sclerosis. Therefore, these compounds are promising options for the treatment of prion diseases.

“Bile Acids Reduce Prion Conversion, Reduce Neuronal Loss, and Prolong Male Survival in Models of Prion Disease” by Leonardo M. Cortez, Jody Campeau, Grant Norman, Marian Kalayil, Jacques Van der Merwe, Debbie McKenzie, and Valerie L. Sim in Journal of Virology doi:10.1128/JVI.01165-15

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