Methamphetamine and prion protein bridging drugs of abuse and neurodegeneration

The cellular prion protein (PrPc) is physiologically expressed within selective brain areas of mammals. Despite not being fully elucidated, a physiological role of PrPc as a co-chaperone resembling that described for alpha-synuclein has been recently suggested. Conformational changes in the secondary structure of PrPc lead to a pathogenic isoform known as scrapie prion protein (PrPsc), which is characterized by high aggregation propensity, high insolubility and protease resistance. Prion protein’s metabolism greatly depends on autophagy and ubiquitin proteasome cell-clearing systems. Methamphetamine (METH), which is a widely abused drug, produces severe neurotoxic effects mainly represented by an abnormal dopamine (DA) activity, which is in turn associated with neurotoxicity and protein misfolding. These effects produce a compensatory increase of chaperones while clogging cell-clearing pathways. When the clearing systems are clogged, high levels of PrPc may lead to its misfolding into PrPsc. Thus, in the present study we explored whether METH administration modifies the amount of PrPc and whether this triggers the appearance of PrPsc. To such an aim, we analyzed the effects of METH and DA administration in PC12 and striatal cells by using SDS-PAGE Coomassie blue, immune-histochemistry and immune-gold electron microscopy. To prove whether METH administration produces PrPsc aggregates, we used antibodies directed against PrP following exposure to proteinase K or sarkosyl, which digest folded PrPc leaving aside PrPsc. We found that METH triggers PrPsc aggregates in DA-containing cells while METH is not effective in primary striatal neurons, which do not produce DA. In the latter cells, exogenous DA is needed to trigger PrPsc accumulation similarly to what happens in DA containing cells under the effects of METH. The present findings, while fostering novel molecular mechanisms involving prion proteins, indicate that, cell pathology similar to prion disorders can be mimicked via a DA-dependent mechanism by a drug of abuse.