Potential cause of Parkinson's disease points to new therapeutic strategy

July 24, 2013, The Scripps Research Institute

Biologists at The Scripps Research Institute (TSRI) have made a significant discovery that could lead to a new therapeutic strategy for Parkinson's disease.

The findings, recently published online ahead of print in the journal Molecular and Cell Biology, focus on an enzyme known as parkin, whose absence causes an early-onset form of Parkinson's disease. Precisely how the loss of this enzyme leads to the deaths of neurons has been unclear. But the TSRI researchers showed that parkin's loss sharply reduces the level of another protein that normally helps protect neurons from stress.

"We now have a good model for how parkin loss can lead to the deaths of neurons under stress," said TSRI Professor Steven I. Reed, who was senior author of the new study. "This also suggests a that might work against Parkinson's and other ."

Genetic Clues

Parkinson's is the world's second-most common neurodegenerative disease, affecting about one million people in the United States alone. The disease is usually diagnosed after the appearance of the characteristic motor symptoms, which include tremor, muscle rigidity and slowness of movements. These symptoms are caused by the loss of neurons in the , a brain region that normally supplies the to other regions that regulate muscle movements.

Most cases of Parkinson's are considered "sporadic" and are thought to be caused by a variable mix of factors including advanced age, subtle genetic influences, chronic neuroinflammation and exposure to pesticides and other toxins. But between 5 and 15 percent of cases arise specifically from inherited gene mutations. Among these, mutations to the are relatively common. Patients who have no functional parkin gene typically develop Parkinson's-like symptoms before age 40.

Parkin belongs to a family of enzymes called ubiquitin ligases, whose main function is to regulate the levels of other proteins. They do so principally by "tagging" their protein targets with ubiquitin molecules, thus marking them for disposal by roving protein-breakers in cells known as proteasomes. Because parkin is a ubiquitin ligase, researchers have assumed that its absence allows some other protein or proteins to evade proteasomal destruction and thus accumulate abnormally and harm neurons. But since 1998, when parkin mutations were first identified as a cause of early-onset Parkinson's, consensus about the identity of this protein culprit has been elusive.

"There have been a lot of theories, but no one has come up with a truly satisfactory answer," Reed said.

Oxidative Stress

In 2005, Reed and his postdoctoral research associate (and wife) Susanna Ekholm-Reed decided to investigate a report that parkin associates with another ubiquitin ligase known as Fbw7. "We soon discovered that parkin regulates Fbw7 levels by tagging it with ubiquitin and thus targeting it for degradation by the proteasome," said Ekholm-Reed.

Loss of parkin, they found, leads to rises in Fbw7 levels, specifically for a form of the protein known as Fbw7?. The scientists observed these elevated levels of Fbw7? in embryonic mouse neurons from which parkin had been deleted, in transgenic mice that were born without the parkin gene, and even in autopsied brain tissue from Parkinson's patients who had parkin mutations.

Subsequent experiments showed that when neurons are exposed to harmful molecules known as reactive oxygen species, parkin appears to work harder at tagging Fbw7? for destruction, so that Fbw7? levels fall. Without the parkin-driven decrease in Fbw7? levels, the neurons become more sensitive to this "oxidative stress"—so that more of them undergo a programmed self-destruction called apoptosis. Oxidative stress, to which dopamine-producing substantia nigra neurons may be particularly vulnerable, has long been considered a likely contributor to Parkinson's.

"We realized that there must be a downstream target of Fbw7? that's important for neuronal survival during oxidative stress," said Ekholm-Reed.

A New Neuroprotective Strategy

The research slowed for a period due to a lack of funding. But then, in 2011, came a breakthrough. Other researchers who were investigating Fbw7's role in cancer reported that it normally tags a cell-survival protein called Mcl-1 for destruction. The loss of Fbw7 leads to rises in Mcl-1, which in turn makes cells more resistant to apoptosis. "We were very excited about that finding," said Ekholm-Reed. The TSRI lab's experiments quickly confirmed the chain of events in neurons: parkin keeps levels of Fbw7? under control, and Fbw7? keeps levels of Mcl-1 under control. Full silencing of Mcl-1 leaves neurons extremely sensitive to oxidative stress.

Members of the team suspect that this is the principal explanation for how parkin mutations lead to Parkinson's disease. But perhaps more importantly, they believe that their discovery points to a broad new "neuroprotective" strategy: reducing the Fbw7?-mediated destruction of Mcl-1 in neurons, which should make more resistant to oxidative and other stresses.

"If we can find a way to inhibit Fbw7? in a way that specifically raises Mcl-1 levels, we might be able to prevent the progressive neuronal loss that's seen not only in Parkinson's but also in other major neurological diseases, such as Huntington's disease and ALS [amyotrophic lateral sclerosis]," said Reed.

Explore further: How disease mutations affect the Parkin protein

More information: Molecular and Cell Biology DOI: 10.1128/MCB.00535-13

Related Stories

How disease mutations affect the Parkin protein

May 31, 2013
Researchers at the MRC Laboratory of Molecular Biology in the United Kingdom have determined the crystal structure of Parkin, a protein found in cells that when mutated can lead to a hereditary form of Parkinson's disease. ...

Parkinson's disease: Parkin protects from neuronal cell death

March 1, 2013
Researchers from Ludwig-Maximilians-Universitaet (LMU) in Munich identify a novel signal transduction pathway, which activates the parkin gene and prevents stress-induced neuronal cell death.

Unleashing the watchdog protein

May 9, 2013
McGill University researchers have unlocked a new door to developing drugs to slow the progression of Parkinson's disease. Collaborating teams led by Dr. Edward A. Fon at the Montreal Neurological Institute and Hospital -The ...

Parkinson's disease: Study of live human neurons reveals the disease's genetic origins

February 7, 2012
Parkinson's disease researchers at the University at Buffalo have discovered how mutations in the parkin gene cause the disease, which afflicts at least 500,000 Americans and for which there is no cure.

Protein linked to Parkinson's disease may regulate fat metabolism

August 25, 2011
National Institutes of Health researchers have found that Parkin, an important protein linked with some cases of early-onset Parkinson's disease, regulates how cells in our bodies take up and process dietary fats.

Recommended for you

Parkinson's disease 'jerking' side effect detected by algorithm

January 8, 2018
A mathematical algorithm that can reliably detect dyskinesia, the side effect from Parkinson's treatment that causes involuntary jerking movements and muscle spasms, could hold the key to improving treatment and for patients ...

New brainstem changes identified in Parkinson's disease

January 4, 2018
A pioneering study has found that patients with Parkinson's disease have more errors in the mitochondrial DNA within the brainstem, leading to increased cell death in that area.

Caffeine level in blood may help diagnose people with Parkinson's disease

January 3, 2018
Testing the level of caffeine in the blood may provide a simple way to aid the diagnosis of Parkinson's disease, according to a study published in the January 3, 2018, online issue of Neurology, the medical journal of the ...

Researchers shed light on why exercise slows progression of Parkinson's disease

December 22, 2017
While vigorous exercise on a treadmill has been shown to slow the progression of Parkinson's disease in patients, the molecular reasons behind it have remained a mystery.

Robotic device improves balance and gait in Parkinson's disease patients

December 19, 2017
Some 50,000 people in the U.S. are diagnosed with Parkinson's disease (PD) every year. The American Institute of Neurology estimates there are one million people affected with this neurodegenerative disorder, with 60 years ...

New findings point to potential therapy for Parkinson's Disease

December 19, 2017
A new study, published in Proceedings of the National Academy of Sciences (PNAS), sheds light on a mechanism underlying Parkinson's disease and suggests that Tacrolimus—an existing drug that targets the toxic protein interaction ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.