Research in Progress

Gene Regulation

Huntingtin on the Job

Dr. Marcy MacDonald of Harvard (whose work is featured in the first section of Research Frontiers) is currently researching the normal function of huntingtin protein in HD. She believes it plays a role in “middle management” in nerve cell signaling in the brain.

The structure of huntingtin is something like that of a Slinkyat can either be free or buried in something else. Researchers believe that huntingtin is an alpha helix (see below for diagram). An alpha helix is a single polypeptide chain that takes on a coiled, cylindrical shape. Huntingtin shuttles between the nucleus and cytoplasm of a nerve cell. While huntingtin is on the move, its front end can associate with various signal transduction proteins including HAP1 and MLK2.

(For more information, click here.)

Fig AE-2,3: alpha helix

Since huntingtin facilitates signal transduction through its interaction with many transcription factors and other proteins, thereby providing support for many processes, researchers consider its function to be like that of a scaffold. Defined in everyday terms, a scaffold is a type of platform that construction workers use when performing tasks at heights above the ground. Several research teams recently proposed the scaffold function of huntingtin after discovering that it does not bind the transcription factor NeuroD (ND); rather, it stimulates ND through HAP1 and MLK2. In other words, huntingtin acts as a platform on which HAP1 and MLK2 can work on stimulating ND.

In her research, MacDonald asked how huntingtin’s facilitation of signaling pathways might contribute to HD pathogenesis. HD pathogenesis is modeled on a cascade, in which the symptoms are triggered by the interaction of mutated huntingtin with an unidentified part of the nerve cell. As the cascade grows longer over time, it eventually leads to nerve cell death. Huntingtin’s role in signaling pathways may occur either at the beginning of the cascade or somewhere downstream on the road to cell death.

In short, mutated huntingtin is a bad manager. When it fails to function properly, its interactions (or lack thereof) with its signaling partners are linked with mechanisms that lead to cell death. However, researchers have shown that huntingtin’s managerial position is necessary, but not sufficient, for triggering the cascade that leads to HD. A biological structure or molecule (such as a protein) is considered to be necessary when scientists remove it from an organism and determine that it is needed in order for a reaction or biological event to take place. A structure or molecule is deemed sufficient if it is relocated within the organism’s body, and the reaction or biological event takes place. Sufficiency can also be determined by whether or not the structure or molecule alone can cause a certain effect. MacDonald used the latter parameter of sufficiency in her huntingtin experiments. When the number and levels of huntingtin partner proteins were altered in humans and mice, the disease cascade was not triggered, so huntingtin’s job as boss was deemed insufficient. In other words, mutant huntingtin alone cannot trigger the disease cascade.

Fig. AE-4 to AE-7: Necessary vs. Sufficient
A biological structure or molecule causes a certain biological event or reaction in a certain cell or tissue.

If a biological structure or molecule is removed from a cell or tissue and the reaction or biological event does not occur, then the structure or molecule is deemed necessary for that event to occur.

Putting the structure or molecule back into the cell or tissue will cause the event to occur:

If a biological structure or molecule is relocated to a different cell or tissue and the given reaction or biological event occurs, then the structure or molecule is deemed sufficient for that even to occur.

Interestingly, the polyglutamine mutation does not greatly interfere with the huntingtin protein’s normal activity. Thus, it seems strange that huntingtin-facilitated signaling is altered in cells expressing mutant huntingtin. According to MacDonald, this occurs because the huntingtin signaling process may play a role somewhere downstream in the disease cascade, at a distance from the mutant huntingtin trigger mechanism. Because the altered signaling pathways are downstream, they further weaken the already compromised nerve cells.

Studying the particulars of huntingtin’s job in middle management may reveal the secrets behind mutant huntingtin’s disease trigger, possibly leading to the prevention of disease cascade initiation.

To read the article, please click here.

Last Modified: 04/12/2007

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