George Rebec. Credit: Indiana University
Indiana University researchers have found that broken communication in a specific part of the brain plays a role in the involuntary physical movements that affect individuals with Huntington's disease.
An incurable, inherited genetic disorder that affects about 300,000 Americans, Huntington's disease involves progressive loss of brain cells and motor function, typically starting in midlife, causing involuntary movement, psychosis and other severe cognitive and emotional problems. The disease is caused by an abnormally long repeating stretch of the amino acid glutamine within a large protein called huntingtin.
The study, led by George Rebec, Chancellor's Professor in the College of Arts and Sciences' Department of Psychological and Brain Sciences at IU Bloomington, suggests a "cell-interaction model" of Huntington's disease, in which this genetic mutation causes erroneous communication between the brain's cerebral cortex and the striatum. The striatum is a portion of the forebrain most affected by Huntington's disease, resulting in physical symptoms.
The results also strongly counter a previously proposed "cell-autonomous model," in which the disease's symptoms stem from the mere presence of the mutated huntingtin gene in the striatum.
"To our knowledge, this is the first evidence in living organisms indicating the mutant huntingtin gene in the brain's cortical output neurons plays an important role in shaping the aberrant activity in striatum—and the related physical symptoms—seen in people with Huntington's disease," Rebec said. "The results suggest a new approach to treatment—targeting a single portion of the brain isn't enough because broken communication between its regions seems to worsen the condition."
There is currently no treatment for Huntington's disease that targets the root cause of the condition, only the symptoms.
"Drugs designed to inhibit movement unfortunately aren't much better than chemical straitjackets," Rebec said. "Ultimately, genetic treatment may be the only answer, but more effective and targeted drug treatments could hold promise in the more immediate future."
To conduct their study, Rebec and collaborators used three mouse models: one that had the mutant huntingtin gene in the striatum but suppressed in the cerebral cortex; a second with Huntington's disease where the mutant huntingtin gene was not suppressed; and a third healthy control group. An approximately equal number of male and female mice were used in the study.
The striatum, which receives messages from the cerebral cortex, is responsible for bodily functions ranging from fine motor control to complex behaviors, such as social interactions. To assess function and communication between these brain regions, scientists measured the electrical firing patterns in the cortex and striatum of the three types of mice as they moved freely. All mice were assessed at regular intervals for several months, including before and after the genetically altered mice began to show signs of Huntington's disease.
The mice were monitored for behaviors such as exploring (rearing or climbing up sloped walls); grooming (face washing and scratching); nest building (including the size of nests and amount of material used); and resting. Nest building served as a particularly significant measure of motor control deterioration and cognitive impartment, as it requires highly coordinated muscular activity.
Monitoring began at 20 weeks of age through 60 weeks of age, a range over which the mice with Huntington's disease began to develop symptoms.
As seen in previous studies of mice with Huntington's disease, the brain developed abnormal electrical activity compared to the healthy group.
But, in the mice that had mutant huntingtin gene suppressed in the cerebral cortex, these symptoms were significantly less severe. Neural activity in the striatum of these mice also was improved over the other mice with Huntington's disease.
The differences in electrical activity were observable in behavior. The mice that had the mutant huntingtin gene suppressed in the cerebral cortex exhibited fewer motor control problems compared to the other mice with Huntington's disease.
"These results strongly indicate that mutant huntingtin gene in the brain's cortical outputs is a key contributor to the physical symptoms observed in people with Huntington's disease," Rebec said. "The partial, but significant, improvement in both striatal neuronal activity and behavior in mice that had the mutant huntingtin gene suppressed in the cerebral cortex suggest that striatal interactions with the cortex play a key role in the motor dysfunctions of Huntington's disease.
"Looking to the future, new treatment approaches will need to be more sensitive to interactions between cells in the brain—the mere presence of the mutant gene in a single region isn't the problem, it's also the interaction between affected regions."
Explore further: Scientists hunt down origin of Huntington's disease in the brain
More information: "Cortical Efferents Lacking Mutant huntingtin Improve Striatal Neuronal Activity and Behavior in a Conditional Mouse Model of Huntington's Disease." J Neurosci. 2015 Mar 11;35(10):4440-51. DOI: 10.1523/JNEUROSCI.2812-14.2015
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George Rebec. Credit: Indiana University
Indiana University researchers have found that broken communication in a specific part of the brain plays a role in the involuntary physical movements that affect individuals with Huntington's disease.
An incurable, inherited genetic disorder that affects about 300,000 Americans, Huntington's disease involves progressive loss of brain cells and motor function, typically starting in midlife, causing involuntary movement, psychosis and other severe cognitive and emotional problems. The disease is caused by an abnormally long repeating stretch of the amino acid glutamine within a large protein called huntingtin.
The study, led by George Rebec, Chancellor's Professor in the College of Arts and Sciences' Department of Psychological and Brain Sciences at IU Bloomington, suggests a "cell-interaction model" of Huntington's disease, in which this genetic mutation causes erroneous communication between the brain's cerebral cortex and the striatum. The striatum is a portion of the forebrain most affected by Huntington's disease, resulting in physical symptoms.
The results also strongly counter a previously proposed "cell-autonomous model," in which the disease's symptoms stem from the mere presence of the mutated huntingtin gene in the striatum.
"To our knowledge, this is the first evidence in living organisms indicating the mutant huntingtin gene in the brain's cortical output neurons plays an important role in shaping the aberrant activity in striatum—and the related physical symptoms—seen in people with Huntington's disease," Rebec said. "The results suggest a new approach to treatment—targeting a single portion of the brain isn't enough because broken communication between its regions seems to worsen the condition."
There is currently no treatment for Huntington's disease that targets the root cause of the condition, only the symptoms.
"Drugs designed to inhibit movement unfortunately aren't much better than chemical straitjackets," Rebec said. "Ultimately, genetic treatment may be the only answer, but more effective and targeted drug treatments could hold promise in the more immediate future."
To conduct their study, Rebec and collaborators used three mouse models: one that had the mutant huntingtin gene in the striatum but suppressed in the cerebral cortex; a second with Huntington's disease where the mutant huntingtin gene was not suppressed; and a third healthy control group. An approximately equal number of male and female mice were used in the study.
The striatum, which receives messages from the cerebral cortex, is responsible for bodily functions ranging from fine motor control to complex behaviors, such as social interactions. To assess function and communication between these brain regions, scientists measured the electrical firing patterns in the cortex and striatum of the three types of mice as they moved freely. All mice were assessed at regular intervals for several months, including before and after the genetically altered mice began to show signs of Huntington's disease.
The mice were monitored for behaviors such as exploring (rearing or climbing up sloped walls); grooming (face washing and scratching); nest building (including the size of nests and amount of material used); and resting. Nest building served as a particularly significant measure of motor control deterioration and cognitive impartment, as it requires highly coordinated muscular activity.
Monitoring began at 20 weeks of age through 60 weeks of age, a range over which the mice with Huntington's disease began to develop symptoms.
As seen in previous studies of mice with Huntington's disease, the brain developed abnormal electrical activity compared to the healthy group.
But, in the mice that had mutant huntingtin gene suppressed in the cerebral cortex, these symptoms were significantly less severe. Neural activity in the striatum of these mice also was improved over the other mice with Huntington's disease.
The differences in electrical activity were observable in behavior. The mice that had the mutant huntingtin gene suppressed in the cerebral cortex exhibited fewer motor control problems compared to the other mice with Huntington's disease.
"These results strongly indicate that mutant huntingtin gene in the brain's cortical outputs is a key contributor to the physical symptoms observed in people with Huntington's disease," Rebec said. "The partial, but significant, improvement in both striatal neuronal activity and behavior in mice that had the mutant huntingtin gene suppressed in the cerebral cortex suggest that striatal interactions with the cortex play a key role in the motor dysfunctions of Huntington's disease.
"Looking to the future, new treatment approaches will need to be more sensitive to interactions between cells in the brain—the mere presence of the mutant gene in a single region isn't the problem, it's also the interaction between affected regions."
Explore further: Scientists hunt down origin of Huntington's disease in the brain
More information: "Cortical Efferents Lacking Mutant huntingtin Improve Striatal Neuronal Activity and Behavior in a Conditional Mouse Model of Huntington's Disease." J Neurosci. 2015 Mar 11;35(10):4440-51. DOI: 10.1523/JNEUROSCI.2812-14.2015
Medical Xpress on facebook
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Scientists hunt down origin of Huntington's disease in the brain
The gene mutation that causes Huntington's disease appears in every cell in the body, yet kills only two types of brain cells. Why? UCLA scientists used a unique approach to switch the gene off in individual ...
New test measures deadly protein in Huntington's disease patients' spinal fluid
A new test has been able to measure for the first time the build-up of a harmful mutant protein in the nervous system of patients during the progression of Huntington's disease (HD). Published today in the Journal of Clinical In ...
Scientists uncover major factor in development of Huntington's disease
Scientists from the Florida campus of The Scripps Research Institute (TSRI) have uncovered a major contributor to Huntington's disease, a devastating progressive neurological condition that produces involuntary movements, ...
Huntington's disease protein helps wire the young brain
The protein that is mutated in Huntington's disease is critical for wiring the brain in early life, according to a new Duke University study.
Novel RNAi therapy silences mutated Huntington's disease gene and reduces symptoms
A targeted gene silencing strategy blocks production of the dysfunctional huntingtin (Htt) protein, the cause of Huntington's disease, a fatal, inherited neurodegenerative disorder. The effectiveness of this ...
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Brain's 'lowly' visual processor is more sophisticated than once thought
When managing, assigning each task to a specialist is often the most efficient strategy. Most researchers regard the brain as working similarly, with each region specialized to a given task. But Johns Hopkins ...
Characteristic pattern of protein deposits in brains of retired NFL players who suffered concussions
A new UCLA study takes another step toward the early understanding of a degenerative brain condition called chronic traumatic encephalopathy, or CTE, which affects athletes in contact sports who are exposed ...
Brain activity boosts processes that promote neural connections
Brain activity affects the way the developing brain connects neurons and a study by researchers at the School of Medicine on the University of Colorado Anschutz Medical Campus and Children's Hospital Colorado ...
Study reveals Internet-style 'local area networks' in cerebral cortex of rats
Researchers sketching out a wiring diagram for rat brains—a field known as "connectomics"—have discovered that its structure is organized like the Internet.
New test measures deadly protein in Huntington's disease patients' spinal fluid
A new test has been able to measure for the first time the build-up of a harmful mutant protein in the nervous system of patients during the progression of Huntington's disease (HD). Published today in the Journal of Clinical In ...
Enhancing mechanism of capsaicin-evoked pain sensation
Drs. Takayama and Tominaga in National Institute for Physiological Sciences (NIPS) (Okazaki Institute for Integrative Bioscience) clarified that an interaction between capsaicin receptor TRPV1 and chloride ...
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