Effects of Parkinson's-disease mutation reversed in cells

Public release date: 16-Aug-2013 [ | E-mail | Share ]

Contact: Jeffrey Norris jeff.norris@ucsf.edu 415-502-6397 University of California - San Francisco

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 Parkinsons disease. A similar approach might ward off cell death in the brains of people afflicted with Parkinsons 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 Parkinsons disease. Loss of PINK1 activity is harmful to the cells power plants, called mitochondria, best known for converting food energy into another form of chemical energy used by cells, the molecule ATP.

In Parkinsons 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 Parkinsons 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 Parkinsons 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 Parkinsons 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 Parkinsons disease caused by another defect. This defect is elevated production of the protein alpha-synuclein, also a cause of some inherited cases of Parkinsons 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 Parkinsons disease in which PINK1 is not mutated, Shokat said.

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Effects of Parkinson's-disease mutation reversed in cells