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
eIF2 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.