DYT1 dystonia is a devastating neurological disorder, producing disabling, sustained abnormal involuntary movements for which reliably effective treatments do not exist. DYT1 dystonia is caused by a three base-pair in-frame GAG mutation in the TOR1A gene that encodes torsinA (TA), an endoplasmic reticulum (ER) glycoprotein belonging to the AAA (ATPases Associated with various cellular Activities) protein family. Using patient tissue, we recently discovered that this mutation causes TA to abnormally relocalize to the nuclear envelope (NE). Furthermore, our data suggest that DYT1 mutant TA (mutTA) acts through a dominant-negative or dominant-toxic effect, by recruiting wild type TA (wtTA) to the NE. Based on these observations, we hypothesize that allele-specific suppression of mutTA will ameliorate the disease. The ability to achieve allele-specific silencing of TA would also be a valuable tool for further characterizing the pathophysiology of DYT1 dystonia. We have already demonstrated that potent allele-specific suppression of TA with RNAi is possible in vitro, and our current proposal represents an attempt to selectively silence TA alleles in vivo. Our main goal is to explore the utility of this strategy as a potential therapy for DYT1 dystonia, but these studies may also uncover important molecular events in disease pathogenesis. We have already generated neural cell lines and transgenic animal models of DYT1 dystonia and the various experimental tools required to achieve allele-specific suppression of TA in vitro and in vivo. These diverse reagents and the complementary skills and commitment of our laboratories to the study and treatment of DYT1 dystonia present us with a unique opportunity to begin to tackle this disease.
| Lee, John H; Tecedor, Luis; Chen, Yong Hong et al. (2015) Reinstating aberrant mTORC1 activity in Huntington's disease mice improves disease phenotypes. Neuron 85:303-15 |
| Monteys, Alex Mas; Spengler, Ryan M; Dufour, Brett D et al. (2014) Single nucleotide seed modification restores in vivo tolerability of a toxic artificial miRNA sequence in the mouse brain. Nucleic Acids Res 42:13315-27 |
| Ramachandran, Pavitra S; Boudreau, Ryan L; Schaefer, Kellie A et al. (2014) Nonallele specific silencing of ataxin-7 improves disease phenotypes in a mouse model of SCA7. Mol Ther 22:1635-42 |
| Ramachandran, Pavitra S; Bhattarai, Sajag; Singh, Pratibha et al. (2014) RNA interference-based therapy for spinocerebellar ataxia type 7 retinal degeneration. PLoS One 9:e95362 |
| Lee, John H; Sowada, Matthew J; Boudreau, Ryan L et al. (2014) Rhes suppression enhances disease phenotypes in Huntington's disease mice. J Huntingtons Dis 3:65-71 |
| Boudreau, Ryan L; Jiang, Peng; Gilmore, Brian L et al. (2014) Transcriptome-wide discovery of microRNA binding sites in human brain. Neuron 81:294-305 |
| Ramachandran, Pavitra S; Keiser, Megan S; Davidson, Beverly L (2013) Recent advances in RNA interference therapeutics for CNS diseases. Neurotherapeutics 10:473-85 |
| Boudreau, Ryan L; Spengler, Ryan M; Hylock, Ray H et al. (2013) siSPOTR: a tool for designing highly specific and potent siRNAs for human and mouse. Nucleic Acids Res 41:e9 |
| Rodriguez-Lebron, Edgardo; Liu, Gumei; Keiser, Megan et al. (2013) Altered Purkinje cell miRNA expression and SCA1 pathogenesis. Neurobiol Dis 54:456-63 |
| Rodríguez-Lebrón, Edgardo; Costa, Maria do Carmo; Costa, Maria doCarmo et al. (2013) Silencing mutant ATXN3 expression resolves molecular phenotypes in SCA3 transgenic mice. Mol Ther 21:1909-18 |
Showing the most recent 10 out of 35 publications
