Metformin reduces prion infection in neuronal cells by enhancing autophagy.

Prion diseases are fatal infectious neurodegenerative disorders in human and animals that are caused by misfolding of the cellular prion protein (PrPC) into the infectious isoform PrPSc. No effective treatment is available for prion diseases. Metformin is a first-line medication for treatment of type 2 diabetes which is known to activate AMPK and induce autophagy through the inhibition of mammalian target of rapamycin (mTOR1) signaling. Metformin was reported to be beneficial in various protein misfolding and neurodegenerative diseases like Alzheimer's and Huntington's diseases. In this study we investigated the anti-prion effect of metformin in persistently prion-infected neuronal cells. Our data showed that metformin significantly decreased the PrPSc load in the treated cells, as shown by less PK resistant PrP in Western blots and reduced prion conversion activity in Real-Time Quaking-Induced Conversion (RT-QuIC) assay in both 22L-ScN2a and RML-ScCAD5 cells. Additionally, metformin induced autophagy as shown by higher levels of LC3-II in treated cells compared with control cells. On the other hand, our mouse bioassay showed that oral metformin at a dose of 2 mg/ml in drinking water had no effect on the survival of prion-infected mice. In conclusion, our findings describe the anti-prion effect of metformin in two persistently prion-infected neuronal cell lines. This effect can be explained at least partially by the autophagy inducing activity of metformin. This study sheds light on metformin as an anti-prion candidate for the combination therapy of prion diseases.

The role of prion strain diversity in the development of successful therapeutic treatments.

Prions are a self-propagating misfolded conformation of a cellular protein. Prions are found in several eukaryotic organisms with mammalian prion diseases encompassing a wide range of disorders. The first recognized prion disease, the transmissible spongiform encephalopathies (TSEs), affect several species including humans. Alzheimer's disease, synucleinopathies, and tauopathies share a similar mechanism of self-propagation of the prion form of the disease-specific protein reminiscent of the infection process of TSEs. Strain diversity in prion disease is characterized by differences in the phenotype of disease that is hypothesized to be encoded by strain-specific conformations of the prion form of the disease-specific protein. Prion therapeutics that target the prion form of the disease-specific protein can lead to the emergence of drug-resistant strains of prions, consistent with the hypothesis that prion strains exist as a dynamic mixture of a dominant strain in combination with minor substrains. To overcome this obstacle, therapies that reduce or eliminate the template of conversion are efficacious, may reverse neuropathology, and do not result in the emergence of drug resistance. Recent advancements in preclinical diagnosis of prion infection may allow for a combinational approach that treats the prion form and the precursor protein to effectively treat prion diseases.