RRC ID 6436
著者 Wang J, Farr GW, Hall DH, Li F, Furtak K, Dreier L, Horwich AL.
タイトル An ALS-linked mutant SOD1 produces a locomotor defect associated with aggregation and synaptic dysfunction when expressed in neurons of Caenorhabditis elegans.
ジャーナル PLoS Genet
Abstract The nature of toxic effects exerted on neurons by misfolded proteins, occurring in a number of neurodegenerative diseases, is poorly understood. One approach to this problem is to measure effects when such proteins are expressed in heterologous neurons. We report on effects of an ALS-associated, misfolding-prone mutant human SOD1, G85R, when expressed in the neurons of Caenorhabditis elegans. Stable mutant transgenic animals, but not wild-type human SOD1 transgenics, exhibited a strong locomotor defect associated with the presence, specifically in mutant animals, of both soluble oligomers and insoluble aggregates of G85R protein. A whole-genome RNAi screen identified chaperones and other components whose deficiency increased aggregation and further diminished locomotion. The nature of the locomotor defect was investigated. Mutant animals were resistant to paralysis by the cholinesterase inhibitor aldicarb, while exhibiting normal sensitivity to the cholinergic agonist levamisole and normal muscle morphology. When fluorescently labeled presynaptic components were examined in the dorsal nerve cord, decreased numbers of puncta corresponding to neuromuscular junctions were observed in mutant animals and brightness was also diminished. At the EM level, mutant animals exhibited a reduced number of synaptic vesicles. Neurotoxicity in this system thus appears to be mediated by misfolded SOD1 and is exerted on synaptic vesicle biogenesis and/or trafficking.
巻・号 5(1)
ページ e1000350
公開日 2009-1-1
DOI 10.1371/journal.pgen.1000350
PMID 19165329
PMC PMC2621352
MeSH Animals Animals, Genetically Modified Bacterial Proteins / metabolism Caenorhabditis elegans / physiology* Gene Expression Regulation* Humans Luminescent Proteins / metabolism Mice Models, Biological Models, Genetic Mutation* Neurons / metabolism* Protein Folding RNA Interference Superoxide Dismutase / genetics* Synapses / metabolism*
IF 5.175
引用数 104
WOS 分野 GENETICS & HEREDITY
リソース情報
線虫 tm903