That toxicity can be corrected, researchers found, at multiple points including RRAS, FNTA/B, PIN1, and PLK1.
“It’s hard to predict a priori where the best intervention point is. I think part of that you have to consider there is, what parts of the pathway are druggable. It may turn out that farnesyltransferase is the most druggable target, that is, say, upstream of RRAS, so it’s a matter of practicality that you would try and intervene there,” Dr. Hughes said.
“What’s interesting is that we now actually have the individual underlying genes that seem to be modifying the Huntington toxicity phenotype, where we can start thinking about them as specific drug targets.”
The laboratories of Drs. Hughes and Ellerby have begun follow-up research on the RRAS pathway.
“We’re very interested in exploring the role of RRAS in cell motility, and in cell migration. These are two processes that I think are critical certainly in development, but also in adult functions, and any cases where cells need to move in order to achieve whatever their functions are,” Dr. Hughes said. “I think that RRAS gives us a nice entry point into these pathways.”
Other longer-term goals, he added, are to continue mining the wealth of data generated by the genome-wide screen, look for other novel pathways for study, with an eye to pharmacologic manipulation. The research team has made available through the PLoS paper all primary screening data from its study: “There’s a lot more information in there to be mined and followed up on.”
[Miller JP, Yates BE, Al-Ramahi I, Berman AE, Sanhueza M, et al. (2012) A Genome-Scale RNA–Interference Screen Identifies RRAS Signaling as a Pathologic Feature of Huntington’s Disease. PLoS Genet 8(11): e1003042. doi:10.1371/journal.pgen.1003042. Accessible at http://www.plosgenetics.org/doi/pgen.1003042.]