Methamphetamine increases prion protein and induces dopamine-dependent expression of protease resistant PrPsc

M. Ferrucci, L. Ryskalin, F. Biagioni, S. Gambardella, C. L. Busceti, A. Falleni, G. Lazzeri, Francesco Fornai

Research output: Contribution to journalArticle

Abstract

The cellular prion protein (PrPc) is physiologically expressed within selective brain areas of mammals. Alterations in the secondary structure of this protein lead to scrapie-like prion protein (PrPsc), which precipitates in the cell. PrPsc has been detected in infectious, inherited or sporadic neurodegenerative disorders. Prion protein metabolism is dependent on autophagy and ubiquitin proteasome. Despite not being fully elucidated, the physiological role of prion protein relates to chaperones which rescue cells under stressful conditions. Methamphetamine (METH) is a widely abused drug which produces oxidative stress in various brain areas causing mitochondrial alterations and protein misfolding. These effects produce a compensatory increase of chaperones while clogging cell clearing pathways. In the present study, we explored whether METH administration modifies the amount of PrPc. Since high levels of PrPc when the clearing systems are clogged may lead to its misfolding into PrPsc, we further tested whether METH exposure triggers the appearance of PrPsc. We analysed the effects of METH and dopamine administration in PC12 and striatal cells by using SDS-PAGE Coomassie blue, immunehistochemistry and immune-gold electron microscopy. To analyze whether METH administration produces PrPsc aggregates we used antibodies directed against PrP following exposure to proteinase K or sarkosyl which digest folded PrPc but misfolded PrPsc. We fond 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.

Original languageEnglish
Pages (from-to)81-97
Number of pages17
JournalArchives Italiennes de Biologie
Volume155
Issue number1-2
DOIs
Publication statusPublished - Jul 1 2017

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Keywords

  • Autophagy
  • Dopamine
  • Drugs of abuse
  • Misfolded proteins
  • Neurodegeneration
  • Striatum

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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