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Nov 30, 2012

Screen Reveals Hundreds of Potential HD Targets

  • A research team has identified hundreds of potential molecular targets linked to toxicity associated with Huntington’s disease (HD), hoping that some of them may lead to new treatments for the fatal disease.

    Using RNAi to reduce the levels of individual cellular proteins, the team carried out a genome-wide screen in a human cell model of HD of more than 7,800 genes viewed as potential drug targets. The human screen was validated in mouse and fruit fly models of the disease. From there, researchers found modifiers of HD toxicity in human cells—including the gene for signaling protein RRAS, whose pathway which will be studied further.

    “The reason that RRAS is really interesting is that it’s involved in cell motility and in neuronal development. And I think that that’s actually a very interesting new area to kind of think about as being pathogenic in Huntington’s disease, or having some sort of role in the disease,” Robert E. Hughes, Ph.D., associate professor at the Buck Institute for Research on Aging, told GEN.

    Dr. Hughes collaborated on the study with two other Buck Institute researchers, Sean Mooney, Ph.D., and Lisa Ellerby, Ph.D.; as well as Juan Botas, Ph.D. of Baylor College of Medicine. The team published its results of the Nov. 29 edition of PLoS Genetics.

    HD results when a mutation in the huntingtin (HTT) gene leads to the accumulation of a toxic protein, leading to neuronal cell death and systemic dysfunction. The genome-wide screen identified multiple components of the RRAS signaling pathway that suppressed the toxicity of mutant HTT protein in human and mouse cell models.

  • Correcting toxicity

    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.]


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