title: Impairment of the autophagic flux in astrocytes intoxicated by trimethyltin.
abstract: Autophagy is a lysosomal catabolic route for protein aggregates and damaged organelles which in different stress conditions, such as starvation, generally improves cell survival. An impairment of this degradation pathway has been reported to occur in many neurodegenerative processes. Trimethyltin (TMT) is a potent neurotoxin present as an environmental contaminant causing tremors, seizures and learning impairment in intoxicated subjects. The present data show that in rat primary astrocytes autophagic vesicles (AVs) appeared after few hours of TMT treatment. The analysis of the autophagic flux in TMT-treated astrocytes was consistent with a block of the late stages of autophagy and was accompanied by a progressive accumulation of the microtubule associated protein light chain 3 (LC3) and of p62/SQSTM1. Interestingly, an increased immunoreactivity for p62/SQSTM1 was also observed in hippocampal astrocytes detected in brain slices of TMT-intoxicated rats. The time-lapse recordings of AVs in EGFP-mCherry-LC3B transfected astrocytes demonstrated a reduced mobility of autophagosomes after TMT exposure respect to control cells. The observed block of the autophagic flux cannot be overcome by known autophagy inducers such as rapamycin or 0.5mM lithium. Although ineffective when used at 0.5mM, lithium at higher concentrations (2mM) was able to protect astrocyte cultures from TMT toxicity. This effect correlated well with its ability to determine the phosphorylation/inactivation of glycogen kinase synthase-3β (GSK-3β).
authors.affiliation: Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Sapienza University, Rome, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Fabrizi
authors.affiliation: Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Sapienza University, Rome, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Pompili
authors.affiliation: Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Sapienza University, Rome, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: De Vito
authors.affiliation: Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Sapienza University, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Somma
authors.affiliation: Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Sapienza University, Rome, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Catizone
authors.affiliation: Department of Experimental Medicine, Second University of Naples, Naples, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Ricci
authors.affiliation: Department of Human Morphology and Applied Biology, Pisa, Italy. Electronic address: paola.lenzi@med.unipi.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Lenzi
authors.affiliation: Department of Human Morphology and Applied Biology, Pisa, Italy; I.R.C.C.S. Neuromed, Pozzilli, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Fornai
authors.affiliation: Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Sapienza University, Rome, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Fumagalli
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D001343:Autophagy / Q000187:drug effects*; D002478:Cells, Cultured; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors; D006624:Hippocampus / Q000378:metabolism; D008094:Lithium / Q000494:pharmacology; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D000071456:Sequestosome-1 Protein / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D014298:Trimethyltin Compounds / Q000037:antagonists & inhibitors / Q000633:toxicity*
chemical_list: D008869:Microtubule-Associated Proteins; D000071456:Sequestosome-1 Protein; C491079:Sqstm1 protein, rat; D014298:Trimethyltin Compounds; C046488:trimethyltin; D008094:Lithium; D000071679:Glycogen Synthase Kinase 3 beta; D020123:Sirolimus
keywords: Astrocytes; Autophagy; Lithium; Neurodegeneration; Trimethyltin