The gene PINK1, discovered in a familial strain of Parkinson’s, is known to help the mitochondria (energy suppliers) of neurons involved in Parkinson’s Disease. PINK1 helps Parkin accumulate in the damaged mitochondria, but prevents further damage and helps the damaged cells to survive and not die. If PINK1 could be increased, it might help keep those neurons functioning longer and prevent progression In people who have mutations of PINK1Parkin is not found in the cells, and neuronal cell death follows.
The team wanted to find a way to strengthen PINK1 and started looking at the way that it is turned on by a particular molecule called ATP. If they could understand how it was turned on, they might be able to find a less direct way to accomplish that task. They started looking at molecules that were very similar to ATP, hoping to find one they could engineer to fit. To their surprise, they found KTP, kinetin triphosphate, a very close relative of ATP that worked. Not only did it turn on PINK1, but it also turned on the mutated forms of PINK1.
To verify that the addition of KTP did the same thing as ATP, they measured the amount of PINK1 activity and also the amount of Parkin that PINK1 brought to the mitochondrial surfaces as well as cell death. Adding the precursor of KTP, kinetin, to the cells of both PINK1 and mutated PINK1 increased the activity, increased the Parkin and lead to less neuronal cell death. Not only will this help people with the familial strain of Parkinson’s Disease, but also people who have the sporadic strain.
The group is now working to demonstrate the effectiveness of this discovery in animal models of Parkinson’s Disease. There are several animal models, but the effects and results in animal models often are not the same as in humans. However, since kinetin and KTP already have Food and Drug Administration approval and are not known to cause adverse reactions in humans, this should both speed up and simplify the process leading to clinical trials in humans.
Nicholas T. Hertz, Amandine Berthet, Martin L. Sos, Kurt S. Thorn, Al L. Burlingame, Ken Nakamura, Kevan M. Shokat. A Neo-Substrate that Amplifies Catalytic Activity of Parkinson’s-Disease-Related Kinase PINK1. Cell, 2013; 154 (4): 737 DOI: 10.1016/j.cell.2013.07.030
Picture Credits: Melbourne Dermatology, Science Direct, Buy Me Beauty, and the above abstract.