Polyglutamine proteins at the pathogenic threshold display neuron-specific aggregation in a pan-neuronal Caenorhabditis elegans model.
The basis of neuron-specific pathogenesis, resulting from the expression of misfolded proteins, is poorly understood and of central importance to an understanding of the cell-type specificity of neurodegenerative disease. In this study, we developed a new model for neuron-specific polyQ pathogenesis in Caenorhabditis elegans by pan-neuronal expression that exhibits polyQ length-dependent aggregation, neurotoxicity, and a pathogenic threshold at a length of 35-40 glutamines. Analysis of specific neurons in C. elegans revealed that only at the threshold length, but not at shorter or longer lengths, polyQ proteins can exist in a soluble state in certain lateral neurons or in an aggregated state in motor neurons of the same animal. These results provide direct experimental evidence that the expression of a single species of a toxic misfolded protein can exhibit a range of neuronal consequences.
Brignull
Heather R
HR
Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University Institute for Neuroscience, Rice Institute for Biomedical Research, Northwestern University, Evanston, Illinois 60208, USA.
Moore
Finola E
FE
Tang
Stephanie J
SJ
Morimoto
Richard I
RI
D000818:Animals; D055592:Biophysical Phenomena; D001703:Biophysics; D017173:Caenorhabditis elegans / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D023421:Models, Animal; D009420:Nervous System / Q000378:metabolism / Q000503:physiopathology*; D009474:Neurons / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D017510:Protein Folding; D014018:Tissue Distribution
D029742:Caenorhabditis elegans Proteins; D010455:Peptides; C097188:polyglutamine