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The molecular biology of Huntington's disease

Published on October 1, 2007 Updated on May 22, 2020   46 min

A selection of talks on Neurology

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0:03
Huntington's disease is a devastating disorder, some of a more dominant neurodegenerative disease, that typically presents with the triad of symptoms. These include abnormal movements, particularly chorea, as you can see in the slide. But perhaps more devastating to the family and to the patients are the psychiatric disturbances, and cognitive deterioration that characterize this disorder. Huntington's disease can present at any age, however, the median age at onset is around 40 years. This results in many cases of Huntington's disease presenting with symptoms or signs after they've already had children.
0:39
Huntington's patients typically die about 15 years after disease onset. The analysis of postmortem brains has provided important insights into the regional specificity of the Huntington mutations effects. The top brain in the slide represents a normal sample, while the bottom brain represents a sample from a Huntington's patient at the end stages of the disease. The CNP in the top panel represent the caudate and putamen. If you look at the Huntington's brain, you can see that these regions are almost completely absent, and there's also significant cortical atrophy. Indeed, loss of cells from the caudate and putamen, and from the cortex represent fairly early events in the disease course.
1:23
The gene causing Huntington's disease was identified in 1993, by a large consortium headed up by Jim Gazelle at Harvard. The Huntington's disease gene encodes a very large protein of more than 3000 amino acids, and this protein is called huntingtin. The Huntington's mutation causes changes close to the amino terminus of this protein. The coding region in the gene at this position comprises a series of uninterrupted CAG trinucleotide repeats. So the sequence reads CAG, CAG, CAG, CAG, CAG etc. Normal individuals have 35 or fewer of these uninterrupted CAGs, while diseases are associated with 36 or more of these repeats. Each of these CAG repeats represents the codon for the amino acids glutamine, so the mutant protein has a very long and abnormally expanded polyglutamine stretch.

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The molecular biology of Huntington's disease

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