[Editors] MIT IDs genes linked to Parkinson’s side effects

[Elizabeth Thomson]

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What causes motor complications of Parkinson’s treatment?
--MIT study identifies genes linked to key side effect; work signals  
new approaches
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For Immediate Release
THURSDAY, JAN. 29, 2009

Contact: Elizabeth A. Thomson, MIT News Office
E: thomson at mit.edu, T: 617-258-5402

Graphic Available

CAMBRIDGE, Mass.--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.”

This study was funded by the Stanley H. and Sheila G. Sydney Fund, the  
National Institutes of Health, National Institute of Child Health and  
Human Development and the National Parkinson Foundation. Coauthors  
Ippolita Canturi-Castelvetri,  Lauren Kett and Anne Young  
(Massachusetts General Hospital); Esen Saka (Hacettepe University,  
Turkey); Christine Keller-McGandy and Ledia Hernandez (MIT); and David  
Standaert (University of Alabama, Birmington) contributed to this study.

--END--

Written by Cathryn Delude, McGovern Institute




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