Huntingtin Protein and Protein Aggregation
Part 3

What Causes the Onset of HD?

How can the structure of huntingtin be altered?

The altered form of huntingtin protein has been found in the autopsied brains of patients who have died of HD. Normal, functioning huntingtin protein contains 10-35 glutamines. (Click here to read more about glutamine expansion numbers.) In contrast, altered HD huntingtin protein (called “Htt" by researchers), contains 40 or more glutamine repeats, resulting from the genetic mutation discussed above. The extended number of glutamine repeats in Htt characterizes HD as one of nine polyglutamine expansion disorders. (To read more about these disorders, click here.)

Because glutamine is a polar, or “charged” molecule, the overabundance of glutamine causes links to form within and between proteins. Htt molecules “stick” to one another, forming strands that are held together by hydrogen bonds. Rather than folding into functional proteins, they develop into tangled, rigid groupings known as protein aggregates. (See Figure P-1.)  These fibrous protein aggregates accumulate and interfere with nerve cell function by entrapping key cell regulatory factors. Researchers are exploring whether protein aggregates are a cause or a consequence of neurodegenerative diseases such as HD. Are aggregates always harmful, causing nerve cell dysfunction and death, or are they simply part of a cellular defense mechanism? We will explore this question throughout this section.

In a process similar to the formation of aggregates, the excess glutamines in Htt can lead to a type of protein bundling known as neuronal inclusions (NI), or inclusion bodies. NIs initially form at the axons and dendrites of nerve cells in specific areas of the human brain, producing the damaged neurons characteristic of HD. Subsequently, an enzyme cuts Htt into smaller fragments which enter the nerve cell nuclei, forming more clumps at the centrosomes. (See Figure P-2.)

Neuronal inclusions cause problems for the cell. They can cause significant changes in cell structure, “trap” and interfere with the normal production of other proteins, and ultimately become toxic to the nerve cell. Thus, the formation of NIs and the neurodegenerative symptoms of HD are clearly linked.

Last Modified: 9-13-02

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