Publication date: Apr 09, 2019
However, when soluble, stable tau misfolds-sometimes the result of a mutation of the gene that expresses it-the resulting protein becomes insoluble and tangled, gumming up the works inside the neuron as a neurofibrillary tangle.
-People had already talked about this gene as possibly involved in Huntington’s disease, which is another neurodegenerative disease,” Kosik says.
Researchers consider RASD2 and its more famous cousin RAS (studied heavily in cancer research) -druggable,” Kosik explains.
Such has been the case for Kosik and the paper’s lead author, postdoctoral researcher Israel Hernandez, who have for years studied tau tangles and the protein coding genes that could contribute to or counteract tau misfolding.
Kosik, Hernandez, and their colleagues’ combination of expertise and curiosity led them to examine a GTPase called Rhes, which the gene RASD2 encodes and research has shown to play a role in the development of Huntington’s disease.
Like its cousins in the Ras superfamily, Rhes is a signaling protein that does its work on the cell surface, where, Kosik explains, a small carbon chain-a farnesyl group-attaches it to the inner membrane through a process called farnesylation.
This attachment has been the target of a couple decades and millions of dollars of cancer research under the assumption that if researchers could interrupt the Ras protein connection to the cell membrane, that would interrupt the signals that cause unregulated growth of tumor cells and other cancer behaviors.
-The drug is very interesting,” Kosik says, -It seems to have a selective effect on only the forms of tau that are predisposed to forming the neurofibrillary tangles. “
To prove the drug was targeting the farnsylated Rhes protein, the scientists introduced into the brains of other mouse models an inhibitory RNA gene that specifically suppresses the production of Rhes.
-This makes us begin to think that although indeed the drug is a general farnesyl transferase inhibitor, one way it’s actually working is by specifically targeting the farnesylation of Rhes,” Kosik says.
And perhaps further down the road, the team is considering a population with frontotemporal dementia in Colombia where Kosik has conducted similar studies in Alzheimer’s disease.