Suppression of autophagy precipitates neuronal cell death following low doses of methamphetamine.
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 alpha-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 alpha-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 alpha-synuclein aggregates and precipitated a bax-mediated mitochondrial apoptosis pathway.
Castino
Roberta
R
Dipartimento di Scienze Mediche, Università A. Avogadro, Novara, Italy.
Lazzeri
Gloria
G
Lenzi
Paola
P
Bellio
Natascia
N
Follo
Carlo
C
Ferrucci
Michela
M
Fornai
Francesco
F
Isidoro
Ciro
C
D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D008694:Methamphetamine / Q000008:administration & dosage* / Q000633:toxicity; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects* / Q000473:pathology; D016716:PC12 Cells; D010539:Permeability / Q000187:drug effects; D051381:Rats; D051028:bcl-2-Associated X Protein / Q000502:physiology
D051028:bcl-2-Associated X Protein; D008694:Methamphetamine