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RNAi Screen Finds Potential Huntington's Disease Drug Targets

NEW YORK (GenomeWeb News) – A genome-wide RNAi screen has turned up hundreds of potential drug targets for Huntington's disease, according to a paper published yesterday in PLoS Genetics.

In addition, the study, presented by researchers from the Buck Institute for Research on Aging and Baylor College of Medicine, indicated a role for the RRAS signaling pathway in the pathology of the disease and suggested that inhibition of the RRAS pathway could be a possible treatment approach for Huntington's disease.

"It seemed to me that there was an unmet need of a comprehensive target-discovery screen [for Huntington's disease]," Buck's Robert Hughes told GenomeWeb Daily News. "We wanted to see if we could map out the target space a little bit, and, hopefully, that'll jump start some target-based drug discovery."

Hughes and his colleagues performed a genome-wide RNAi screen to unearth modifiers of mutant huntingtin toxicity in a human cell-based model of the disease. From this screen, the researchers uncovered a number of cellular proteins that could reduce mutant huntingtin toxicity. Of the siRNAs tested, 130 reduced toxicity by one standard deviation below the mean, while eight reduced it by two standard deviations below the mean.

Through an ontological analysis of those 130 siRNAs, the researchers found a number of cellular processes, both known and novel, linked to Huntington's disease, including hydrolase activity, proteolysis, and peptidase activity. The researchers noted in the paper that uncovering processes known to be involved in the disease underscored that "the cell-model and modifier results are generally relevant to molecular aspects of the disease."

The researchers then homed in on RRAS and its signaling pathway — which had not been previously linked to Huntington's disease — for further study. RRAS activates a number of downstream targets, including RAF1, and is involved in cell motility and neuronal development.

"We became particularly interested in RRAS just because it had a fairly potent effect on the toxicity of mutant huntingtin when knocked down, and it also had some interesting biology around it," said Hughes.

He and his colleagues further validated the role of members of the RRAS signaling pathway in Huntington's disease by examining its effects in other models of the disease, finding abnormal activation of RRAS and RAF1 in both cellular and mouse models of the disease.

In addition, the researchers reported that mutant huntingtin and RRAS co-localize to lamellipodia and perinuclear regions of cells as well as in the striatum of mice, "suggest[ing] that mutant huntingtin may exert some direct effect on RRAS through protein interaction or presence in a shared protein complex."

Then, using a farnesyltransferase inhibitor, the researchers showed that inhibiting the Ras signaling pathway suppressed mutant huntingtin toxicity.

While the results were encouraging, Hughes noted that it is a long and difficult road to get from a possible drug target to having a therapeutic. However, he said that knowing that RRAS responds to extracellular ligands, as it does when it mediates neuronal migration, is helpful. "Given that we know that this particular protein [and] its activity can be activated by extracellular ligands, that provides an opportunity for drugging it," he added.

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