PIP4Kγ Inhibition Shown to Reduce mHtt Levels, Displays Promise for Huntington

March 30, 2018

Using the NCT-504 compound to inhibit cell-signaling activity in PIP4Kγ resulted in an increase in autophagy in connective tissue cells from patients with HD.

Juan Marugan, PhD

Blocking the phosphatidylinositol-5-phosphate 4-kinase, type II γ (PIP4Kγ) enzyme has been revealed to reduce the impact of Huntington disease (HD) in both cell and animal models, new research shows.1

This inhibition triggers a recycling system to lessen malformation and toxic protein buildup in brain cells, according to the work conducted by Juan Marugan, PhD, acting branch chief and group leader of the National Institutes of Health’s (NIH) National Center for Advancing Translational Sciences (NCATS), and colleagues from Baylor College of Medicine and the University of Michigan. This increase in autophagy ability could aid cells in combating HD’s effects.

“These results provide important insights into understanding the biology of a rare, devastating neurological disease,” Marugan said.2 “PIP4Kγ inhibitors could be useful for Huntington and other neurodegenerative disorders such as Alzheimer and Parkinson diseases, which also are marked by the accumulation of toxic proteins.”

PIP4Kγ, a lipid kinase expressed by PIP4K2C, was additionally revealed to reduce mutant huntingtin (mHtt) protein levels in the cells of patients with HD, as well as to clear the aggregates of mHtt in the neuronal cell models.

With knowledge of PIP4Kγ’s role in cell signaling, the team of researchers tested thousands of compounds to assess their impact on that process. They found that NCT-504—a compound previously proven to lower mHtt levels and improve cell survival—to inhibit cell signaling in a multitude of cells, including connective tissue cells from patients with HD. That inhibition increased autophagy and reduced clusters of proteins associated with HD.

Marugan and colleagues noted 2 major alterations following this inhibition: An increase in autophagic flux, and an increase in the levels of 3 phosphoinositide signaling lipids. “It is tempting to speculate that the changes in [phosphoinositide] upregulate autophagic flux, and thereby lower mHtt levels,” they wrote.

The team added that this PIP4Kγ-inhibition induced autophagic flux increase is likely in part due to the resulting impact on phosphoinositide lipids, as PIP4Kγ has been predicted to convert PI5P to PI9(4,5)P2. Although they noted that exactly which of these PI5P cellular pools are substrates for PIP4Kγ is unclear.

The potential of PIP4Kγ inhibition could extend beyond HD, as well. “[Alzheimer] disease and [Parkinson] disease, in particular, are also mediated by the accumulation of toxic protein aggregates, whose catabolism by autophagy might rescue stressed neurons,” the team wrote.

Additionally, the investigators wished to know what the effects of completely turning off PIP4Kγ activity genetically would be. Using 2 models of fruit flies, a common HD archetype, they observed that silencing PIP4Kγ resulted in a reduction of mHtt proteins that had accumulated in the neurons. This lessened damage and improved mobility, providing additional evidence for the enzyme as a possible target.

“These findings open the door to a new disease-modifying approach for this disorder and validate PIP4Kγ as a druggable target,” Marugan and others concluded. Dose-response studies need to be conducted to fully assess the enzyme.

Marugan added that they plan to continue seeking molecules with efficacy in inhibiting PIP4Kγ. “We want to develop better molecules that could intervene in Huntington’s and potentially other diseases,” he said.

REFERENCES

1. Al-Ramahi I, Giridharan SSP, Chen Y, et al. Inhibition of PIP4Ky ameliorates the pathological effects of mutant huntingtin protein. eLife. 2017;6:e29123. doi: 10.7554/eLife.29123

2. NCATS-Led Team Finds Potential Strategy to Fight Huntington’s Disease [press release]. Bethesda, MD: NCATS; January 2018. https://ncats.nih.gov/news/releases/2018/huntington. Accessed March 30, 2018.