Dopaminergic neuronal loss and motor deficits in Caenorhabditis elegans overexpressing human alpha-synuclein.
Overexpression of human alpha-synuclein in model systems, including cultured neurons, drosophila and mice, leads to biochemical and pathological changes that mimic synucleopathies including Parkinson's disease. We have overexpressed both wild-type (WT) and mutant alanine53-->threonine (A53T) human alpha-synuclein by transgenic injection into Caenorhabditis elegans. Motor deficits were observed when either WT or A53T alpha-synuclein was overexpressed with a pan-neuronal or motor neuron promoter. Neuronal and dendritic loss were accelerated in all three sets of C. elegans dopaminergic neurons when human alpha-synuclein was overexpressed under the control of a dopaminergic neuron or pan-neuronal promoter, but not with a motor neuron promoter. There were no significant differences in neuronal loss between overexpressed WT and A53T forms or between worms of different ages (4 days, 10 days or 2 weeks). These results demonstrate neuronal and behavioral perturbations elicited by human alpha-synuclein in C. elegans that are dependent upon expression in specific neuron subtypes. This transgenic model in C. elegans, an invertebrate organism with excellent experimental resources for further genetic manipulation, may help facilitate dissection of pathophysiologic mechanisms of various synucleopathies.
Lakso
Merja
M
Department of Neurobiology, A. I. Virtanen Institute, Kuopio University, Finland.
Vartiainen
Suvi
S
Moilanen
Anu-Maarit
AM
Sirviö
Jouni
J
Thomas
James H
JH
Nass
Richard
R
Blakely
Randy D
RD
Wong
Garry
G
D000818:Animals; D030801:Animals, Genetically Modified; D001522:Behavior, Animal; D001681:Biological Assay / Q000706:statistics & numerical data; D017173:Caenorhabditis elegans; D002452:Cell Count; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D017930:Genes, Reporter; D006801:Humans; D009043:Motor Activity / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000503:physiopathology*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D051843:Synucleins; D051844:alpha-Synuclein
D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D004298:Dopamine