Suppression of autophagy precipitates neuronal cell death following low doses of methamphetamine

Roberta Castino, Gloria Lazzeri, Paola Lenzi, Natascia Bellio, Carlo Follo, Michela Ferrucci, Francesco Fornai, Ciro Isidoro

Research output: Contribution to journalArticlepeer-review

Abstract

Methamphetamine abuse is toxic to dopaminergic neurons, causing nigrostriatal denervation and striatal dopamine loss. Following methamphetamine exposure, the number of nigral cell bodies is generally preserved, but their cytoplasm features autophagic-like vacuolization and cytoplasmic accumulation of α-synuclein-, ubiquitin- and parkin-positive inclusion-like bodies. Whether autophagy is epiphenomenal or it plays a role in the mechanism of methamphetamine toxicity and, in the latter case, whether its role consists of counteracting or promoting the neurotoxic effect remains obscure. We investigated the signaling pathway and the significance (protective vs. toxic) of autophagy activation and the convergence of the autophagic and the ubiquitin-proteasome pathways at the level of the same intracellular bodies in a simple cell model of methamphetamine toxicity. We show that autophagy is rapidly up-regulated in response to methamphetamine. Confocal fluorescence microscopy and immuno-electron microscopy studies demonstrated the presence of α-synuclein aggregates in autophagy-lysosomal structures in cells exposed to methamphetamine, a condition compatible with cell survival. Inhibition of autophagy either by pharmacologic or genetic manipulation of the class III Phosphatidylinositol-3 kinase-mediated signaling prevented the removal of α-synuclein aggregates and precipitated a bax-mediated mitochondrial apoptosis pathway.

Original languageEnglish
Pages (from-to)1426-1439
Number of pages14
JournalJournal of Neurochemistry
Volume106
Issue number3
DOIs
Publication statusPublished - Aug 2008

Keywords

  • α-synuclein
  • Apoptosis
  • Beclin 1
  • Lysosomes
  • Neurodegeneration
  • Vps34-class III PI3k

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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