Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Effects of Parkinson's-disease mutation reversed in cells

19.08.2013
UCSF study shows potential for new treatment strategy

UC San Francisco scientists working in the lab used a chemical found in an anti-wrinkle cream to prevent the death of nerve cells damaged by mutations that cause an inherited form of Parkinson’s disease. A similar approach might ward off cell death in the brains of people afflicted with Parkinson’s disease, the team suggested in a study reported online in the journal Cell on August 15.

The achievement marks a pharmacologic milestone as the first highly specific targeting of a member of an important class of enzymes called kinases to increase rather than to inhibit their activity, according to UCSF chemist Kevan Shokat, PhD, the senior scientist on the study. The research raises hope that similar pharmaceutical strategies might be used for combatting other diseases, including diabetes and cancer, he said.

Mutations that cause malfunction of the targeted enzyme, PINK1, are directly responsible for some cases of early-onset Parkinson’s disease. Loss of PINK1 activity is harmful to the cell’s power plants, called mitochondria, best known for converting food energy into another form of chemical energy used by cells, the molecule ATP.

In Parkinson’s disease, poorly performing mitochondria have been associated with the death of dopamine-producing nerve cells in a region of the brain called the substantia nigra, which plays a major role in control of movement. Loss of these cells is a hallmark of Parkinson’s disease and the cause of prominent symptoms including rigidity and tremor.

A UCSF team led by Shokat, a Howard Hughes Medical Institute Investigator, used the chemical, called kinetin, to increase mutant PINK1 enzyme activity in nerve cells to near normal levels.

“In light of the fact that mutations in PINK1 produce Parkinson’s disease in humans, the finding that kinetin can speed mutated PINK1 activity to near normal levels raises the possibility that kinetin may be used to treat these patients,” Shokat said.

The researchers also found that, in nerve cells with normal PINK1, kinetin boosted enzyme activity beyond typical levels. This finding may be relevant for the most common forms of Parkinson’s disease, in which PINK1 is not mutated, because a previous study showed that similar overactivity of PINK1 can slow the development of abnormal movement in a fruit-fly model of Parkinson’s disease caused by another defect. This defect is elevated production of the protein alpha-synuclein, also a cause of some inherited cases of Parkinson’s disease.

The demonstration in the new study that PINK1 can be boosted in human nerve cells that lack PINK1 mutations therefore suggests that kinetin might also have therapeutic potential in common cases of Parkinson’s disease in which PINK1 is not mutated, Shokat said.

Parkinson’s disease is the second most common neurodegenerative disease after Alzheimer’s disease, and the 14th leading cause of death in the United States, according to the U.S Centers for Disease Control and Prevention. Current treatments primarily aim to boost availability of dopamine to brain regions where dopamine-producing nerve cells have been lost.

Although many drugs that inhibit the activity of kinases have been developed over the past decade, including 15 currently approved to treat cancer, Shokat said none has yet been marketed to directly boost activity of a kinase.

The breakthrough in revving up PINK1 activity pharmacologically stemmed from Shokat’s unconventional approach. He targeted the enzyme’s “substrate,” a molecule that binds to an enzyme and undergoes a quick chemical transformation as a result. PINK1 uses ATP as a substrate, and the chemical reaction helps PINK1 in turn drive the activation of another enzyme, called Parkin.

Both of these enzymes are among a small number that previously have been strongly linked to Parkinson’s disease. PINK1 and Parkin act together to monitor the health of mitochondria, and help trigger repair or disposal of damaged mitochondria within the cells, thereby promoting cell survival.

“Therapeutic approaches for enhancing the activity of PINK1 had not been considered, because scientists had not conceived of the idea of developing a new substrate for the enzyme,” Shokat said.

“We found that a small molecule, called KTP, speeds chemical reactions catalyzed by PINK1 better than ATP, the natural substrate. That kind of better-than-natural response is essentially unheard of.”

KTP is too big to fit into other kinases, Shokat said, but PINK1 has a larger ATP “pocket” to hold KTP.

After discovering the potential of KTP, the researchers then determined that kinetin is converted to KTP within cells. Experimentally, kinetin, which can cross blood vessels to get into the brain, has been given by mouth to treat a rare, genetic, neurological disease called familial dysautonomia.

Other researchers on the UCSF study include graduate student Nicholas Hertz, PhD; post-doctoral fellows Martin Sos, PhD and Amandine Berthet, PhD; UCSF faculty members Ken Nakamura, MD, PhD from the Gladstone Institute, and Kurt Thorn, PhD, and Al Burlingame, PhD.

The research was funded by the National Institutes for Health and by the Michael J. Fox Foundation.

Hertz and Shokat are inventors on a patent application related to kinetin and PINK1. UCSF has licensed the patent application to Mitokinin LLC, and Hertz and Shokat are cofounders and members of the company.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy, a graduate division with nationally renowned programs in basic biomedical, translational and population sciences, as well as a preeminent biomedical research enterprise and two top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children’s Hospital.

Jeffrey Norris | EurekAlert!
Further information:
http://www.ucsf.edu

More articles from Life Sciences:

nachricht The dense vessel network regulates formation of thrombocytes in the bone marrow
25.07.2017 | Rudolf-Virchow-Zentrum für Experimentelle Biomedizin der Universität Würzburg

nachricht Fungi that evolved to eat wood offer new biomass conversion tool
25.07.2017 | University of Massachusetts at Amherst

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Carbon Nanotubes Turn Electrical Current into Light-emitting Quasi-particles

Strong light-matter coupling in these semiconducting tubes may hold the key to electrically pumped lasers

Light-matter quasi-particles can be generated electrically in semiconducting carbon nanotubes. Material scientists and physicists from Heidelberg University...

Im Focus: Flexible proximity sensor creates smart surfaces

Fraunhofer IPA has developed a proximity sensor made from silicone and carbon nanotubes (CNT) which detects objects and determines their position. The materials and printing process used mean that the sensor is extremely flexible, economical and can be used for large surfaces. Industry and research partners can use and further develop this innovation straight away.

At first glance, the proximity sensor appears to be nothing special: a thin, elastic layer of silicone onto which black square surfaces are printed, but these...

Im Focus: 3-D scanning with water

3-D shape acquisition using water displacement as the shape sensor for the reconstruction of complex objects

A global team of computer scientists and engineers have developed an innovative technique that more completely reconstructs challenging 3D objects. An ancient...

Im Focus: Manipulating Electron Spins Without Loss of Information

Physicists have developed a new technique that uses electrical voltages to control the electron spin on a chip. The newly-developed method provides protection from spin decay, meaning that the contained information can be maintained and transmitted over comparatively large distances, as has been demonstrated by a team from the University of Basel’s Department of Physics and the Swiss Nanoscience Institute. The results have been published in Physical Review X.

For several years, researchers have been trying to use the spin of an electron to store and transmit information. The spin of each electron is always coupled...

Im Focus: The proton precisely weighted

What is the mass of a proton? Scientists from Germany and Japan successfully did an important step towards the most exact knowledge of this fundamental constant. By means of precision measurements on a single proton, they could improve the precision by a factor of three and also correct the existing value.

To determine the mass of a single proton still more accurate – a group of physicists led by Klaus Blaum and Sven Sturm of the Max Planck Institute for Nuclear...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Closing the Sustainability Circle: Protection of Food with Biobased Materials

21.07.2017 | Event News

»We are bringing Additive Manufacturing to SMEs«

19.07.2017 | Event News

The technology with a feel for feelings

12.07.2017 | Event News

 
Latest News

NASA mission surfs through waves in space to understand space weather

25.07.2017 | Physics and Astronomy

Strength of tectonic plates may explain shape of the Tibetan Plateau, study finds

25.07.2017 | Earth Sciences

The dense vessel network regulates formation of thrombocytes in the bone marrow

25.07.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>