What causes motor complications of Parkinson's treatment?

January 29, 2009
The Graybiel Lab caused Parkinson's disease in rats by depleting dopamine in the right side of the striatum, the brain region that drives the abnormal movements in the disease, leaving the left side as the control. Treating the rats with L-DOPA induced dyskinesia of the limbs controlled by the dopamine-depleted striatum, mimicking the side effect of L-DOPA treatment in humans. Compared to the normal, control side, the treated side shows significantly reduced expression of CalDAG-GEFI but abnormally high levels of CalDAG-GEFII. This imbalance may contribute to the involuntary movements of dyskinesia. Image courtesy / Jill Crittenden, McGovern Institute for Brain Research at MIT

People with Parkinson's disease commonly suffer a slowing or freezing of movement caused by the death of neurons that make dopamine, a key chemical that allows brain cells to send and receive messages essential to voluntary movements. Patients regain the ability to move, seemingly miraculously, by taking L-DOPA or related drugs that mimic the missing dopamine. After a few years on L-DOPA, however, most patients again lose motor control — but in an opposite way. Instead of too little, there is too much movement, like involuntary nodding and rocking — side effects known as L-DOPA-induced dyskinesias.

"L-DOPA-induced dyskinesias are a major problem for patients, and there is a great need to help with these drug side effects," said MIT Institute Professor Ann Graybiel, a prominent Parkinson's researcher at the McGovern Institute for Brain Research at MIT.

Graybiel and her colleagues have identified two molecules whose expression in the brain is altered in the brains of animals with L-DOPA-induced dyskinesias. The results may lead to new approaches to the treatment of dyskinesias in Parkinson's patients, of which there are more than 1 million in the United States alone.

"We're very excited because these genes are concentrated in precisely the places that lose dopamine in Parkinson's disease, so they might be reasonable targets to go after therapeutically," Graybiel said. This research was published Jan. 26 in the advance online issue of Proceedings of the National Academy of Sciences.

The two related genes, named CalDAG-GEFI and CalDAG-GEFII, which are believed to be involved in signaling inside neurons, are expressed in the striatum, a brain structure essential for the control of movement and the main target of the dopamine-containing nerve tract that degenerates in Parkinson's disease.

In a rat model of Parkinson's disease, the two genes showed opposite changes when the animals were treated with L-DOPA. CalDAG-GEFI showed decreased expression while CalDAG-GEFII was increased.

"Moreover, the changes in the rat brain were proportional to the severity of the drug-induced dyskinesias. The more exaggerated the movements, the greater the dysregulation of these genes," said first author Jill Crittenden, a research scientist in the Graybiel Lab.

These CalDAG-GEF genes are thought to work by controlling the activity of other important signaling molecules (Ras, Rap and ERK) that are expressed in many different parts of the body and have many different biological functions. Other labs have shown that inhibiting Ras or ERK in animal models of dyskinesias prevents these involuntary movements.

"But because Ras and ERK do so many things, they are not promising drug targets because blocking them would probably have many unwanted effects," Crittenden said. "Because the CalDAG-GEF molecules control ERK and because they are so enriched in the very part of the brain that controls these involuntary movements, regulating them could have therapeutic value for dyskinesia without causing other problems."

Source: Massachusetts Institute of Technology

Explore further: Schizophrenia disrupts the brain's entire communication system, researchers say

Related Stories

Schizophrenia disrupts the brain's entire communication system, researchers say

October 17, 2017
Some 40 years since CT scans first revealed abnormalities in the brains of schizophrenia patients, international scientists say the disorder is a systemic disruption to the brain's entire communication system.

Biologists identify possible new strategy for halting brain tumors

September 29, 2017
MIT biologists have discovered a fundamental mechanism that helps brain tumors called glioblastomas grow aggressively. After blocking this mechanism in mice, the researchers were able to halt tumor growth.

Gene immunotherapy protects against multiple sclerosis in mice

September 21, 2017
A potent and long-lasting gene immunotherapy approach prevents and reverses symptoms of multiple sclerosis in mice, according to a study published September 21st in the journal Molecular Therapy. Multiple sclerosis is an ...

Seeing hope: FDA panel considers gene therapy for blindness (Update)

October 9, 2017
A girl saw her mother's face for the first time. A boy tore through the aisles of Target, marveling at toys he never knew existed. A teen walked onto a stage and watched the stunned expressions of celebrity judges as he wowed ...

Neuron types in brain are defined by gene activity shaping their communication patterns

September 21, 2017
In a major step forward in research, scientists at Cold Spring Harbor Laboratory (CSHL) today publish in Cell a discovery about the molecular-genetic basis of neuronal cell types. Neurons are the basic building blocks that ...

Alcohol use affects levels of cholesterol regulator through epigenetics

September 20, 2017
In an analysis of the epigenomes of people and mice, researchers at Johns Hopkins Medicine and the National Institutes of Health report that drinking alcohol may induce changes to a cholesterol-regulating gene.

Recommended for you

Engineered protein treatment found to reduce obesity in mice, rats and primates

October 19, 2017
(Medical Xpress)—A team of researchers with pharmaceutical company Amgen Inc. report that an engineered version of a protein naturally found in the body caused test mice, rats and cynomolgus monkeys to lose weight. In their ...

New procedure enables cultivation of human brain sections in the petri dish

October 19, 2017
Researchers at the University of Tübingen have become the first to keep human brain tissue alive outside the body for several weeks. The researchers, headed by Dr. Niklas Schwarz, Dr. Henner Koch and Dr. Thomas Wuttke at ...

Cancer drug found to offer promising results in treating sepsis in test mice

October 19, 2017
(Medical Xpress)—A combined team of researchers from China and the U.S. has found that a drug commonly used to treat lung cancer in humans offers a degree of protection against sepsis in test mice. In their paper published ...

Tracing cell death pathway points to drug targets for brain damage, kidney injury, asthma

October 19, 2017
University of Pittsburgh scientists are unlocking the complexities of a recently discovered cell death process that plays a key role in health and disease, and new findings link their discovery to asthma, kidney injury and ...

Study reveals key molecular link in major cell growth pathway

October 19, 2017
A team of scientists led by Whitehead Institute has uncovered a surprising molecular link that connects how cells regulate growth with how they sense and make available the nutrients required for growth. Their work, which ...

Inflammation trains the skin to heal faster

October 18, 2017
Scars may fade, but the skin remembers. New research from The Rockefeller University reveals that wounds or other harmful, inflammation-provoking experiences impart long-lasting memories to stem cells residing in the skin, ...

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.