title: A proteomic analysis of MCLR-induced neurotoxicity: implications for Alzheimer's disease.
abstract: Cyanobacteria-derived microcystin-leucine-arginine (MCLR), commonly characterized as a hepatotoxin, has recently been found to show neurotoxicity, but the exact mechanism is still unknown. To further our understanding of the neurotoxic effects of MCLR and the mechanisms behind it, we used two-dimensional gel electrophoresis and mass spectrometry analysis to identify global protein profiles associated with MCLR-induced neurotoxicity. MCLR-treated hippocampi showed alterations in proteins involved in cytoskeleton, neurodegenerative disease, oxidative stress, apoptosis, and energy metabolism. After validation by Western blot and quantitative real-time PCR, the expressions of three proteins related to neurodegenerative disease, septin 5, α-internexin, and α-synuclein, were identified to be altered by MCLR exposure. Based on our proteomic analysis that MCLR toxicity might be linked to neurodegeneration, we examined the activity of serine/threonine-specific protein phosphatases (PPs), which are markers of neurodegenerative disease. MCLR was found to induce inhibition of PPs and abnormal hyperphosphorylation of the neuronal microtubule-associated protein tau. This was found to lead to impairment of learning and memory, accompanied by severe histological damage and neuronal apoptosis in the hippocampal CA1 regions of rats. Our results support the hypothesis that MCLR could induce neurotoxic effects, the reason for which could be attributed to the disruption of the cytoskeleton, oxidative stress, and inhibition of PPs in the hippocampus. Moreover, MCLR was found to induce tau hyperphosphorylation, spatial memory impairment, neuronal degenerative changes, and apoptosis, suggesting that this cyanotoxin may contribute to Alzheimer's disease in humans.
authors.affiliation: College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China.
authors.forename: Guangyu
authors.initials: G
authors.lastname: Li
authors.forename: Fei
authors.initials: F
authors.lastname: Cai
authors.forename: Wei
authors.initials: W
authors.lastname: Yan
authors.forename: Cairong
authors.initials: C
authors.lastname: Li
authors.forename: Jianghua
authors.initials: J
authors.lastname: Wang
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000523:psychology; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015180:Electrophoresis, Gel, Two-Dimensional; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007381:Intermediate Filament Proteins / Q000378:metabolism; D008297:Male; D008568:Memory; D052998:Microcystins / Q000633:toxicity*; D009410:Nerve Degeneration; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000523:psychology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D040901:Proteomics / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D015203:Reproducibility of Results; D058112:Septins / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013997:Time Factors; D051844:alpha-Synuclein / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D007381:Intermediate Filament Proteins; C489131:Mapt protein, rat; D052998:Microcystins; D009419:Nerve Tissue Proteins; C497606:Snca protein, rat; D051844:alpha-Synuclein; C046643:alpha-internexin; D016875:tau Proteins; C049865:cyanoginosin-LA; D010749:Phosphoprotein Phosphatases; C491613:Septin5 protein, rat; D058112:Septins