Corporate Banner
Satellite Banner
Proteomics
Scientific Community
 
Become a Member | Sign in
Home>News>This Article
  News
Return

Effects of Parkinson’s Disease Mutation Reversed in Cells

Published: Friday, August 23, 2013
Last Updated: Friday, August 23, 2013
Bookmark and Share
UCSF study used chemical commonly found in anti-wrinkle cream.

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. The team suggests that a similar approach might ward off cell death in the brains of people afflicted with Parkinson’s disease.

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.

Boosting Activity of Kinase

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.


Further Information

Join For Free

Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 3,000+ scientific posters on ePosters
  • More than 4,500+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Cat Stem Cell Therapy Gives Humans Hope
By the time Bob the cat came to the UC Davis veterinary hospital, he had used up most of his nine lives.
Monday, February 08, 2016
Crowdfunding the Fight Against Cancer
From budding social causes to groundbreaking businesses to the next big band, crowdfunding has helped connect countless worthy projects with like-minded people willing to support their efforts, even in small ways. But could crowdfunding help fight cancer?
Monday, February 08, 2016
Clearest Ever Images of Enzyme that Plays Key Roles in Aging, Cancer
UCLA-led research on telomerase could lead to new strategies for treating disease
Monday, October 19, 2015
Crop Cure
Scientists in new center to use medical research techniques to help food crops withstand drought and climate change.
Friday, October 16, 2015
Industry-Sponsored Academic Inventions Spur Increased Innovation
Analysis questions assumption that corporate support skews science toward inventions that are less useful than those funded by the government or non-profit organizations.
Monday, March 24, 2014
Structure of Key Pain-Related Protein Unveiled
In a technical tour de force, scientists have determined, at near-atomic resolution, the structure of a protein that plays a central role in the perception of pain and heat.
Friday, December 06, 2013
Chemical Signature for Fast Form of Parkinson's Found
The physical decline experienced by Parkinson's disease patients eventually leads to disability and a lower quality of life.
Monday, November 25, 2013
New Insights into How Proteins Regulate Genes
Researchers have developed a new way to parse and understand how special proteins called "master regulators" read the genome, and consequently turn genes on and off.
Monday, October 21, 2013
Cell Growth Discovery Has Implications for Targeting Cancer
The way cells divide to form new cells is controlled in previously unsuspected ways.
Monday, October 21, 2013
Discovery Could Lead to Saliva Test for Pancreatic Cancer
The disease is typically diagnosed through an invasive and complicated biopsy.
Tuesday, October 15, 2013
Tuberculosis and Parkinson’s Disease Linked by Unique Protein
UCSF researchers seek way to boost protein to fight both diseases.
Wednesday, September 11, 2013
Dentistry School Receives $5M to Study Saliva Biomarkers
Imagine having a sample of your saliva taken at the dentist's office, and then learning within minutes whether your risk for stomach cancer is higher than normal.
Thursday, August 15, 2013
Scientists Devise Innovative Method to Profile and Predict the Behavior of Proteins
A class of proteins that are made up of multiple, interlocking molecular components, enzymes perform a variety of tasks inside each cell.
Friday, August 09, 2013
Immune System Molecule Promotes Tumor Resistance
A team of scientists has shown for the first time that a signaling protein involved in inflammation also promotes tumor resistance to anti-angiogenic therapy.
Tuesday, August 06, 2013
Failure to Destroy Toxic Protein Contributes to Progression of Huntington’s Disease
Gladstone-led study also finds target that boosts protein clearance, prolongs cell life.
Tuesday, July 23, 2013
Scientific News
FNIH Launches Project to Evaluate Biomarkers in Cancer Patients
Company has announced that it has launched a new project to evaluate the effectiveness of liquid biopsies as biomarkers in colorectal cancer patients.
HIV Particles Used to Trap Intact Mammalian Protein Complexes
Belgian scientists from VIB and UGent developed Virotrap, a viral particle sorting approach for purifying protein complexes under native conditions.
Potential “Good Fat” Biomarker
New method to measure the activity of energy consuming brown fat cells could ease the testing weight loss drugs.
Computational Model Finds New Protein-Protein Interactions
Researchers at University of Pittsburgh have discovered 500 new protein-protein interactions (PPIs) associated with genes linked to schizophrenia.
New Insights into Gene Regulation
Researchers have solved the three-dimensional structure of a gene repression complex that is known to play a role in cancer.
Controlling RNA in Living Cells
Modular, programmable proteins can be used to track or manipulate gene expression.
Soy Shows Promise as Natural Anti-Microbial Agent
Soy isoflavones and peptides may inhibit the growth of microbial pathogens that cause food-borne illnesses, according to a new study from University of Guelph researchers.
Potential Target for Revolutionary Antibiotics
An international team of including the Lomonosov Moscow State University researchers discovered which enzyme enables Escherichia coli bacterium (E. coli) to breathe.
DNA Barcodes Gone Wild
A team of researchers at University of Toronto’s Donnelly Centre and Sinai Health System’s Lunenfeld-Tanenbaum Research Institute (LTRI) has developed a new technology that can stitch together DNA barcodes inside a cell to simultaneously search amongst millions of protein pairs for protein interactions.
Biomarkers for Profiling Prostate Cancer Patients
Exiqon A/S has announced the publication of validation of prognostic microRNA biomarkers for the aggressiveness of prostate cancer in independent cohorts.
Scroll Up
Scroll Down
SELECTBIO

Skyscraper Banner
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
3,000+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,500+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FOR FREE!