Suppression of autophagy precipitates neuronal cell death following low doses of methamphetamine |
| |
Authors: | Castino Roberta Lazzeri Gloria Lenzi Paola Bellio Natascia Follo Carlo Ferrucci Michela Fornai Francesco Isidoro Ciro |
| |
Affiliation: | Dipartimento di Scienze Mediche, UniversitàA. Avogadro, Novara, Italy; Dipartimento di Morfologia Umana e Biologia Applicata, Universitàdi Pisa, Pisa, Italy; IRCC S INM Neuromed, Pozzilli, IS, Italy; BRMA, Centro di Biotecnologie per la Ricerca Medica Applicata, Novara, Italy |
| |
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. |
| |
Keywords: | α-synuclein apoptosis beclin 1 lysosomes neurodegeneration Vps34-class III PI3k |
本文献已被 PubMed 等数据库收录! |
|