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PMID:19165329

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Citation

Wang, J, Farr, GW, Hall, DH, Li, F, Furtak, K, Dreier, L and Horwich, AL (2009) An ALS-linked mutant SOD1 produces a locomotor defect associated with aggregation and synaptic dysfunction when expressed in neurons of Caenorhabditis elegans. PLoS Genet. 5:e1000350

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.

Links

PubMed PMC2621352 Online version:10.1371/journal.pgen.1000350

Keywords

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

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

CAEEL:G5EFT5

involved_in

GO:0035966: response to topologically incorrect protein

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00248994

P

Seeded From UniProt

complete

CAEEL:O16303

involved_in

GO:0035966: response to topologically incorrect protein

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00248994

P

Seeded From UniProt

complete

CAEEL:HS110

involved_in

GO:0035966: response to topologically incorrect protein

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00248994

P

Seeded From UniProt

complete

CAEEL:Q19228

involved_in

GO:0035966: response to topologically incorrect protein

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00248994

P

Seeded From UniProt

complete

CAEEL:Q20752

involved_in

GO:0035966: response to topologically incorrect protein

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00248994

P

Seeded From UniProt

complete


See also

References

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