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Toxic Interactions from Neighboring Cells May Be Necessary for Huntington’s disease


For release: Tuesday, September 27, 2005

A new study suggests that interactions between different cells are critical for the development of Huntington’s disease (HD) and perhaps other neurodegenerative diseases.   This study provides the first genetic evidence that cell-cell interactions may be a necessary step in the onset of HD symptoms in a mouse model. This knowledge may lead to new therapeutic strategies to treat HD.

“Although people had a hunch for a long time that cell-cell interactions might lead to the disease state, there was no direct evidence in an in-vivo (living) model,” says senior author William Yang, of the Jane and Terry Semel Institute of Neuroscience and Human Behavior at the University of California, Los Angeles. “This is the first direct genetic evidence to demonstrate that pathological interactions between cells can significantly contribute to brain cell death in a living mouse model of Huntington’s disease.”  The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) and results were published in the May 5, 2005, issue of Neuron.*

HD is an inherited disease that causes changes in a person’s ability to control movements, thinking and feelings.   It results from genetically programmed degeneration of neurons in certain areas of the brain. 

In the study, researchers compared two mouse models.  One model exhibited a toxic fragment of the mutated human HD protein expressed throughout all types of neurons in the mouse brain.  The second model restricted the HD protein to pyramidal neurons in the cortex, a brain region that is usually severely affected by Huntington’s disease.  Pyramidal cells are the major cells within the cortex and are known to degenerate in HD.

Mice with the mutated human HD gene expression only in the cortex’s pyramidal cells showed few signs of the disease.  However, mice with the mutated gene expressed in all neurons demonstrated problems with motor control and showed visible pathological changes in the brain including degeneration of the pyramidal brain cells. The authors hypothesize that toxic interactions among cells throughout the brain are necessary for degeneration of neurons to occur in HD. “The mutant HD proteins exert their influence on brain cells located near target cells that are destined to degenerate in HD.  These neighboring cells then interact with the target cells to spark the disease.  Toxicity from the outside may be as much to blame for the disease as that on the inside of the target brain cells,” says Dr. Yang. 

The next step for Dr. Yang and collaborators is to determine which of the neighboring cells actually are important in initiating the disease process in HD.  The researchers will test the idea that the cortex is affected early in the disorder and then toxic signals are sent to the target area of the striatum (a brain area known for its role in motor control and motor learning) which leads to the movement problems and severe degeneration of striatal neurons in HD.   The researchers hope that identifying these cell-cell interactions in HD may lead to a better understanding of other neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Pathological cell-cell interactions could prove to be a general characteristic of these and other neurodegenerative diseases.

Once a cellular relationship can be established, the researchers hope to discover novel options for treating and preventing HD.  The researchers are also planning future studies to understand the molecular basis for such interactions and how these interactions might be controlled.  Understanding the basic biology underlying cell interactions in normal and diseased brains may lead to future treatments that can either block harmful or restore useful cell-cell interactions in degenerative disorders.

The NINDS is a component of the National Institutes of Health (NIH) within the Department of Health and Human Services and is the nation’s primary supporter of biomedical research on the brain and nervous system.  The NIH is comprised of 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services.  It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and investigates the causes, treatments, and cures for both common and rare diseases.  For more information about NIH and its programs, visit http://www.nih.gov.

*Gu X, Li C, Wei W, Lo V, Gong S, Li SH, Iwasato T, Itohara S, Li XJ, Mody I, Heintz N, Yang XW. “Pathological cell-cell interactions elicited by a neuropathogenic form of mutant Huntington contribute to cortical pathogenesis in HD mice.” Neuron, May 5, 2005, Vol.46, pp.433-444.

-By Michelle D. Jones-London, Ph.D.

Last Modified January 31, 2007