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The Journal of Neuroscience, July 19, 2006, 26(29):7597-7606; doi:10.1523/JNEUROSCI.0990-06.2006

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Neurobiology of Disease
Polyglutamine Proteins at the Pathogenic Threshold Display Neuron-Specific Aggregation in a Pan-Neuronal Caenorhabditis elegans Model

Heather R. Brignull, Finola E. Moore, Stephanie J. Tang, and Richard I. Morimoto

Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University Institute for Neuroscience, Rice Institute for Biomedical Research, Northwestern University Evanston, Illinois 60208

Correspondence should be addressed to Dr. Richard I. Morimoto, Northwestern University, Department of Biochemistry, 2145 Sheridan Road, Tech MG90, Evanston, IL 60208. Email: r-morimoto{at}northwestern.edu

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.

Key words: polyglutamine; aggregates; neurotoxicity; C. elegans; FRET; FRAP

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Received Oct. 13, 2005; revised June 5, 2006; accepted June 10, 2006.

Correspondence should be addressed to Dr. Richard I. Morimoto, Northwestern University, Department of Biochemistry, 2145 Sheridan Road, Tech MG90, Evanston, IL 60208. Email: r-morimoto{at}northwestern.edu

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