Local proteins associated with methamphetamine-induced nigrostriatal dopaminergic neurotoxicity.
The present study aimed to examine the proteins involved in the methamphetamine (MA)-induced nigrostriatal dopaminergic toxicity. Infusion of anisomycin into striatum and substantia nigra both abolished the MA-induced striatal dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) depletions, indicating a critical role of local protein synthesis in determining such dopaminergic toxicity. Moreover, local protein synthesis blockade reversed this neurotoxicity via a temperature-independent mechanism. We then employed a proteomic approach, two-dimensional gel electrophoresis (2-DE) in conjunction with mass spectrometry analysis, to identify the protein candidates associated with the MA-induced neurotoxicity. In striatal samples, 2-DE analysis revealed that the intensities of nine protein spots were altered by MA treatment. Mass spectrometry analysis allowed us to identify five proteins, including an up-regulated protein, alpha-synuclein, and four down-regulated proteins, ATPase, F-actin capping protein beta subunit, ubiquitin carboxy-terminal hydrolase/PGP 9.5, and peroxidase. MA-altered expression levels of alpha-synuclein and ubiquitin carboxy-terminal hydrolase/PGP 9.5 in striata were confirmed by western blotting analysis. Taken together, these results suggest that local up-regulation of alpha-synuclein and down-regulation of ubiquitin carboxy-terminal hydrolase/PGP 9.5 could be linked to the MA-induced dopaminergic terminal toxicity.
Liao
Pao-Chi
PC
Department of Environmental and Occupational Health, National Cheng Kung University College of Medicine, Tainan, Taiwan.
Kuo
Yu-Min
YM
Hsu
Hen-Chia
HC
Cherng
Chienfang G
CG
Yu
Lung
L
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D015153:Blotting, Western; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D015180:Electrophoresis, Gel, Two-Dimensional; D005334:Fever / Q000139:chemically induced; D008297:Male; D013058:Mass Spectrometry; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009498:Neurotoxins / Q000494:pharmacology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism*; D051843:Synucleins; D025801:Ubiquitin / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000378:metabolism; D051844:alpha-Synuclein
D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D011500:Protein Synthesis Inhibitors; C497605:Snca protein, mouse; D051843:Synucleins; D025801:Ubiquitin; D051844:alpha-Synuclein; D015102:3,4-Dihydroxyphenylacetic Acid; D008694:Methamphetamine; D000841:Anisomycin; D043222:Ubiquitin Thiolesterase; C496976:Uchl1 protein, mouse; D004298:Dopamine