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Study Sheds Light On The Origin Of Huntington's Disease Within The Brain

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Justine Alford

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790 Study Sheds Light On The Origin Of Huntington's Disease Within The Brain
UCLA. Mouse brain showing the cortex (pink) and striatum (yellow).

Scientists from UCLA have used a mouse model to shed light on the brain regions targeted by the mutant gene which causes Huntington’s disease. In doing so they have suggested therapeutic targets that could be exploited in order to slow disease progression. The study has been published in Nature Medicine.

Huntington’s disease (HD) is an incurable and fatal neurodegenerative disease where extensive cell death in particular areas of the brain leads to a progressive loss in motor and cognitive functions. The two main areas of the brain that experience decline are the cortex and the striatum, although the striatum experiences greater degeneration than the cortex.


HD is caused by a mutation in the huntingtin gene where a repeat in the DNA sequence has expanded, causing an abnormal huntingtin protein to be produced. Intriguingly, mutant huntingtin is expressed in all cells of the body but only seems to cause cell death in the neurons of the cortex and striatum, and the reason behind this has puzzled scientists for years. It’s also unknown as to whether cortical degeneration plays a role in HD.

Pivotal to understanding more about HD is discerning the particular cells in which the mutation is contributing to disease. To tackle this, the scientists used transgenic mice which were engineered to express the mutant huntingtin. These mice display similar disease progression and brain atrophy to humans.

Next, they selectively switched off the mutant gene in either neurons of the striatum or cortex alone, or in both at the same time. For each condition they measured disease progression and brain deterioration.

They found that if they switched off the gene in neurons of the cortex only, a modest improvement in motor and psychiatric-like behavioral impairments was observed, but neurodegeneration still occurred. However, if they switched off the gene in neurons of both brain areas the mice were relieved not only of the motor and behavioral deficits but brain atrophy as well. Switching off the gene in both areas also restored the function of the connections (synapses) between striatal neurons to a greater extent than if only one of the areas was targeted.


"We were surprised to learn that cortical neurons play a key role in initiating aspects of the disease in the brain," said Nan Wang, co-lead author of the study. 

According to X William Yang, lead researcher of the study, their results suggest that the mutation is interrupting communication between these two brain areas. “Reducing the defective gene in the cortex normalized this communication and helped lessen the disease’s impact on the striatum,” he explained in a news release. The results also critically suggest that in order to be effective, therapies should target mutant gene expression in both the striatum and cortex.

In order to take this further the team will investigate how this mutation is affecting the function of neurons within these particular areas, and search for possible therapeutic targets that may slow disease progression. 


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