Methamphetamine produces neuronal inclusions in the nigrostriatal system and in PC12 cells

Francesco Fornai, Paola Lenzi, Marco Gesi, Paola Soldani, Michela Ferrucci, Gloria Lazzeri, Loredana Capobianco, Giuseppe Battaglia, Antonio De Blasi, Ferdinando Nicoletti, Antonio Paparelli

Research output: Contribution to journalArticlepeer-review

Abstract

Mice treated with the psychostimulant methamphetamine (MA) showed the appearance of intracellular inclusions in the nucleus of medium sized striatal neurones and cytoplasm of neurones of the substantia nigra pars compacta but not in the frontal cortex. All inclusions contained ubiquitin, the ubiquitin activating enzyme (E1), the ubiquitin protein ligase (E3-like, parkin), low and high molecular weight heat shock proteins (HSP 40 and HSP 70). Inclusions found in nigral neurones stained for α-synuclein, a proteic hallmark of Lewy bodies that are frequently observed in Parkinson's disease and other degenerative disorders. However, differing from classic Lewy bodies, MA-induced neuronal inclusions appeared as multilamellar bodies resembling autophagic granules. Methamphetamine reproduced this effect in cultured PC12 cells, which offered the advantage of a simple cellular model for the study of the molecular determinants of neuronal inclusions. PC12 inclusions, similar to those observed in nigral neurones, were exclusively localized in the cytoplasm and stained for α-synuclein. Time-dependent experiments showed that inclusions underwent a progressive fusion of the external membranes and developed an electrodense core. Inhibition of dopamine synthesis by α-methyl-p-tyrosine (αMpT), or administering the antioxidant S-apomorphine largely attenuated the formation of inclusions in PC12 cells exposed to MA. Inclusions were again observed when αMpT-treated cells were loaded with L-DOPA, which restored intracellular dopamine levels.

Original languageEnglish
Pages (from-to)114-123
Number of pages10
JournalJournal of Neurochemistry
Volume88
Issue number1
Publication statusPublished - Jan 2004

Keywords

  • α-synuclein
  • Methamphetamine
  • Neuronal inclusions
  • Parkin
  • Proteasome
  • Ubiquitin

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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