Expanded hexanucleotide repeats in the human C9ORF72 gene cause frontotemporal dementia and amyotrophic lateral sclerosis (Boeve et al., 2012; Renton et al., 2011). The normal and abnormal mechanisms of action of this human disease gene are not fully understood. We are characterizing phenotypes associated with mutations in F18A1.6, the C. elegans homolog of C9ORF72. We found that feeding RNAi of F18A1.6 caused developmental delay, while the insertion/deletion allele
ok3062 did not. F18A1.6(RNAi) also reduced locomotor behavior in a thrashing assay, compared to empty-vector control. Surprisingly,
ok3062 animals displayed increased thrashing, compared to N2. To better understand the cellular basis of the locomotion phenotypes, we are now conducting pharmacological and neuronal GFP reporter assays. We are also generating transgenic animals to test the ability of C9ORF72 to rescue F18A1.6-associated phenotypes and to test the effects of expressing expanded hexanucleotide repeats in C. elegans. References Boeve, K. B. Boylan, N. R. Graff-Radford, M. DeJesus-Hernandez, D. S. Knopman, O. Pedraza, and P. Vemuri (2012). Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72. Brain 135, 765-783. Renton, E. Majounie, A. Waite, J. Simon-Sanchez, S. Rollinson, J. R. Gibbs, J. C. Schymick, and H. Laaksovirta (2011). A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72, 257-268.