Similarities between methamphetamine toxicity and proteasome inhibition

F. Fornai, P. Lenzi, M. Gesi, M. Ferrucci, G. Lazzeri, L. Capobianco, A. De Blasi, G. Battaglia, F. Nicoletti, S. Ruggieri, A. Paparelli

Research output: Contribution to journalArticle

Abstract

The monoamine neurotoxin methamphetamine (METH) is commonly used as an experimental model for Parkinson's disease (PD). In fact, METH-induced striatal dopamine (DA) loss is accompanied by damage to striatal nerve endings arising from the substantia nigra. On the other hand, PD is characterized by neuronal inclusions within nigral DA neurons. These inclusions contain α-synuclein, ubiquitin, and various components of a metabolic pathway named the ubiquitin-proteasome (UP) system, while mutation of genes coding for various components of the UP system is responsible for inherited forms of PD. In this presentation we demonstrate for the first time the occurrence of neuronal inclusions in vivo in the nigrostriatal system of the mouse following administration of METH. We analyzed, in vivo and in vitro, the shape and the fine structure of these neuronal bodies by using transmission electron microscopy. Immunocytochemical investigation showed that these METH-induced cytosolic inclusions stain for ubiquitin, α-synuclein, and UP-related molecules, thus sharing similar components with Lewy bodies occurring in PD, with an emphasis on enzymes belonging to the UP system. In line with this, blockade of this multicatalytic pathway by the selective inhibitor epoxomycin produced cell inclusions with similar features. Moreover, using a multifaceted pharmacological approach, we could demonstrate the need for endogenous DA in order to form neuronal inclusions.

Original languageEnglish
Pages (from-to)162-170
Number of pages9
JournalAnnals of the New York Academy of Sciences
Volume1025
DOIs
Publication statusPublished - 2004

Keywords

  • Dopamine
  • Methamphetamine
  • Neuronal inclusions
  • Ubiquitin-proteasome pathway
  • Ultrastructure

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Fornai, F., Lenzi, P., Gesi, M., Ferrucci, M., Lazzeri, G., Capobianco, L., De Blasi, A., Battaglia, G., Nicoletti, F., Ruggieri, S., & Paparelli, A. (2004). Similarities between methamphetamine toxicity and proteasome inhibition. Annals of the New York Academy of Sciences, 1025, 162-170. https://doi.org/10.1196/annals.1316.021