Bile acids reduce prion conversion, reduce neuronal loss, and prolong male
survival in models of prion disease.
Leonardo M. Corteza,b, Jody Campeaua,b, Grant Normana,b, Marian Kalayila,b,
Jacques Van der Merwea, Debbie McKenziea,c and Valerie L. Sim#,a,b,c,d
+ Author Affiliations Centre for Prions and Protein Folding Diseases,
Edmonton, Alberta, Canadaa Department of Medicine, Division of Neurology,
University of Alberta, Edmonton, Alberta, Canadab Department of Biological
Sciences, University of Alberta, Edmonton, Alberta, Canadac Neuroscience and
Mental Health Institute, University of Alberta, Edmonton, Alberta, Canadad
ABSTRACT
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 (ALS). 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 PSD-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 FDA-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 multi-modal 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 FDA-approved for use in
humans with primary biliary cirrhosis. They have recently been proven
efficacious in human ALS. Therefore, these compounds are promising options for
the treatment of prion diseases.
Self-Propagative Replication of Ab Oligomers Suggests Potential
Transmissibility in Alzheimer Disease
Received July 24, 2014; Accepted September 16, 2014; Published November 3,
2014
Singeltary comment ;
Sunday, May 3, 2015
PRION2015 FORT COLLINS
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