New Data Suggest Enzyme Blockage Could Fight HD


A study published in the journal eLife suggests that blocking an enzyme could reduce levels of the mutant huntingtin (mHTT) protein.

A study published in the journal eLife suggests that blocking an enzyme could reduce levels of the mutant huntingtin (mHTT) protein.1

The study, “Inhibition of PIP4Ky ameliorates the pathological effects of mutant huntingtin protein,” was supported by NCATS via its Intramural Research Program. The American Heart Association and the University of Michigan also contributed. The results conclude that blockage of the enzyme could clear toxic aggregates of the protein and serve as a potentially effective therapeutic strategy against the neurodegenerative disease.

One of the main problems associated with HD is the body’s inability to discard cellular waste. While a healthy cell is capable of ridding itself of cellular waste, including mutant proteins, in a process called autophagy, patients with HD do not have the ability. This can result in the buildup of the mHTT protein.

Lead study author Ismael Al-Ramahi of the Jan and Dan Duncan Neurological Research Institute, at Texas Children's Hospital and Baylor College of Medicine and a team of researchers found that inhibiting activity of PIP4Kγ (Phosphatidylinositol-5-phosphate 4-kinase, type II γ), a lipid kinase expressed by the PIP4K2C gene, increased autophagy, reduced mHtt protein levels in cells from patients with HD and cleared aggregates of mHtt in neuronal cell models of the condition.

At the initiation of this study, it was understood that PIP4Ky plays a role in cell signaling, a process by which cells send chemical messages to communicate information for biological activity. The team used the NCT-504 compound — which has been proven in historical studies to lower levels of the mHtt protein and improve cell survival – to inhibit that activity in an array of cells, including connective tissue cells from patients with HD and human and mouse neurons from disease models. The inhibition increased recycling activity and reduced the clusters of HD proteins.

“These results provide important insights into understanding the biology of a rare, devastating neurological disease,” said co-author Juan Marugan, Ph.D., acting branch chief and group leader of the NCATS Chemical Genomics Center in a press release. “PIP4Kγ inhibitors could be useful for Huntington’s and other neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases, which also are marked by the accumulation of toxic proteins.”2

Additionally, the researchers wanted to see what would happen if they genetically turned off PIP4Ky activity. Using fruit flies, which have been known to mimic many of the effects of HD, as 2 different models, it was observed that silencing PIP4Ky activity reduced the amount of the mHtt protein that accumulated in the neurons. Thus, damage to the neurons was lessened and the mobility was vastly improved, providing further evidence that this enzyme could be used as a therapeutic target.

The research team intends to continue the evaluation of molecules that show efficacy in blocking this enzyme. Marugan noted: “We want to develop better molecules that could intervene in Huntington’s and potentially other diseases.”

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  1. Al-Ramahi I, Srinivas Panapakkam Giridharan S, Chen YC, Patnaik S, 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 [news release]. Bethesda, MD: NCATS; January 2018. Accessed March 30, 2018.
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