CHICAGO, Jan. 12 (Xinhua) -- A team of researchers from several universities and research institutions has identified a new drug target for treating Huntington's disease, an inherited fatal neurological disorder.
The researchers started with a drug screen using a cell model of Huntington's disease. They individually tested thousands of small molecules, applying them to cells that expressed the toxic portion of the mutant protein.
The screen pinpointed one small molecule, named NCT-504 that appeared to have the desired effect by inhibiting a specific enzyme in the cells: a lipid kinase called PIP4Kgamma, namely phosphatidylinositol-5-phosphate 4-kinase, type II gamma.
As a lipid kinase inhibitor, NCT-504 decreases the effect of the PIP4Kgamma enzyme in the cell. When the activity PIP4Kgamma was suppressed, researchers noticed increased cellular levels of three lipids that are involved in an important process to clean up damaged proteins in cells, called autophagy.
The increase in these three lipids may account for an observed increase in autophagic activity, which in turn may be improving the cells' ability to clear out the protein aggregates that cause Huntington's disease.
"We predicted it would impact one of the lipids, but it turned out that it was also elevating two other lipids that we have studied extensively," said Lois Weisman, a professor of cell and developmental biology at the University of Michigan (UM) Medical School.
The researchers then tested this genetic model in fruit flies to see if the enzyme could have the same effect in a living organism. They decreased activity of PIP4Kgamma in fruit flies that had the Huntington's disease mutation, and saw a decrease in the effects of two fly models of Huntington's disease.
"What's most exciting here is that not only can the animals tolerate the lack of this enzyme, but it's actually making them better," Weisman said.
"This very open, basic-research type of screen was key to this finding," Weisman said. "And based on the mild increase in autophagy that we saw in the cell-based models, we think it might be important for other neurodegenerative diseases as well, including Alzheimer's."
In the next step, the researchers will test the model in mammals and determine whether a decrease in this enzyme can deter Huntington's disease in more complex organisms.
The findings was published in the journal eLife in December.