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Chemical Reverses the Effects of a Rare Parkinsonís Genetic Mutation

New laboratory studies have discovered that an over-the-counter substance called kinetin can protect the dopamine neurons involved in Parkinson’s disease (PD) and reverse the effects of a rare genetic mutation that can cause the disease.  The results appear in the August 15 online edition of Cell.

Mutations in the gene PINK1 can cause some rare instances of early-onset PD. In healthy cells, this gene works in tandem with another gene linked to PD, Parkin, to help cells to dispose of damaged mitochondria (the powerplant of the cell). In some cases of PD, since PINK1 cannot be properly turned on, it cannot do its job of removing damaged mitochondria. As a result, mitochondria become toxic and the cell may die, leading to PD.

Researchers at the University of California, San Francisco, led by Kevan M. Shokat, Ph.D., set out to find a way to boost the activity of mutated PINK1 as a potential PD therapy. Using biochemical techniques, they investigated the activity of the PINK1 protein to understand how mutations might leave it unable to be turned on. Then, in studies with cells, including human neurons, they searched for alternative molecules that could turn PINK1 back on.  

Results

  • The scientists found that a molecule called kinetin triphosphate or KTP can bind to mutated PINK1 and restore its ability to work.
  • KTP also can boost the activity of normal PINK1.
  • When cells are given a precursor of KTP, called kinetin, they can convert it to KTP, and restore the function of mutated PINK1.
  • Increasing PINK1 activity can prevent the death of neurons in culture.

What Does It Mean?

The results of this study raise the possibility that kinetin, a plant hormone, may be useful in reversing the harmful effect of low PINK1 activity. Therefore, it is possible that this molecule can reverse PD symptoms in those rare cases of people who develop PD because of PINK1 mutations. If this is indeed correct, it would also be important to see if boosting PINK1 activity may help people who develop PD because of other genetic mutations (e.g. in the gene Parkin) and in those who developed PD without any identifiable mutation.

Much work remains to be done before kinetin can be developed into a possible PD therapy. But it has potential to move quickly for two reasons: first, it has already been shown to be well-tolerated in humans in clinical trials for other diseases and second, it has been shown to penetrate the brain by crossing the blood brain barrier in studies in mice, an important ability for a PD drug. The next steps following this work are to study its effects in laboratory mice with PD caused by mutations in the PINK1 gene and to study its effect on neurons derived from skin cells of people with PD with and without PINK1 mutations.

The study also has broader implications. The PINK1 protein is a type of enzyme called a kinase, and kinase enzymes are disrupted in many diseases. More than a dozen drugs have been developed to reduce the activity of overactive kinase enzymes, but this is the first evidence to show that low kinase enzyme activity can be increased.  This strategy might aid in developing therapies for some cancers and forms of diabetes.

Reference: Hertz NT, Berthet A, Sos ML, Thorn KS, Burlingame AL, Nakamura K, Shokat KM (2013) A Neo-Substrate that Amplifies Catalytic Activity of Parkinson's-Disease-Related Kinase PINK1. Cell 154:737–747.  DOI: 10.1016/j.cell.2013.07.030 http://dx.doi.org/10.1016/j.cell.2013.07.030

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Source Date: Sep 09 2013