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Huntington’s disease
For most people, Huntington’s disease (HD) is the kind of affliction that sounds familiar and yet means nothing. In our normal lives, it’s easy to remain ignorant about something that seems so distant and unimportant—that is, until it affects you or someone you know.
HD is a genetically inherited disease that affects specific regions of the brain. Classified as a neurodegenerative condition, any parent with a mutation in the gene that encodes huntingtin (an aptly named protein ultimately responsible for the disease, not to be confused with Huntington's disease itself) has a fifty percent chance of passing on the mutation to each child.
Affected patients can exhibit a wide range of symptoms, from difficulties in movement to emotional and cognitive changes; in the most severe cases, patients become increasingly aggressive and show hypersexual activity. The progression of HD is usually long and drawn out over a period of ten to fifteen years, ultimately ending in death. Perhaps most disconcerting of all, in most cases the symptoms of HD do not manifest until later in life, usually after child-bearing years.
The mutation that causes this crippling disorder is as simple as it is deadly. In one gene on chromosome four, any average Joe walking down the street has a certain number of repeating sequences in the DNA that code for huntingtin. Like a recipe, this DNA sequence tells Joe’s protein assembly machinery to create huntingtin, a protein normally containing anywhere from six to thirty-six glutamines (essential building blocks) strung together like boxcars on a train.
When the DNA sequence has a mutation that signals greater than 36 glutamine repeats, the cellular protein-producing machinery follows instructions as usual and creates a protein with an expanded number of repeats: a longer train. Huntingtin with more than 36 glutamine repeats is toxic and eventually leads to HD.
The number of repeats that an affected individual has can predict various aspects of the disease: there is an inverse correlation between the number of repeats and the severity as well as age of onset of HD. For example, someone with forty glutamine repeats will most likely develop the disease later in life and have milder symptoms compared to someone with eighty repeats. In fact, in the most severe cases where HD pathology can be seen in children, the gene that encodes huntingtin can have over 100 repeats.
Aggregates and HD
In 1997 a group of researchers made an amazing discovery that would answer some questions about the toxic role of expanded glutamine repeats. This important finding shed light on the current understanding of HD, but at the same time opened hundreds of new doors to still darkened rooms with more mysterious and baffling questions. When looking at transgenic mice whose DNA had been altered to include part of the HD gene, Davies and colleagues found that the mutated protein with greater than 36 repeats moved into the nucleus and clumped together to form insoluble aggregates.
The nucleus, which houses DNA and acts as the central processing unit for cells, contained aggregates made up of mutant huntingtin. Immediately scientists began to consider that these clumps of protein could account for the disease symptoms.
The idea that aggregates caused HD was supported by the fact that although huntingtin in its mutant form is expressed and found all over the brain and body, HD pathology is limited to two specific regions of the brain, the same two regions where aggregates were found.
Since the nucleus is an important region that directs many cellular functions and houses hereditary information, it seemed entirely conceivable that these aggregates could reek havoc on many cellular processes. Like a dump truck stalled in the middle of an interstate, these aggregates might prevent the normal movement of molecules within the nucleus.
For example, say that during some critical point in a brain cell's life one specific protein is essential for survival. A transcription factor must find its way to a specific region of DNA to initiate production of the necessary protein. On its way there it encounters a roadblock of aggregated huntingtin and never "turns on" the protein production, thus the cell dies.
Of course the above example is purely theoretical and much simplified, but one could imagine various scenarios where aggregates would block important molecular trafficking in the nucleus. Up until recently much of the HD research focused on elucidating what role aggregates play in accelerating cellular death, all the while assuming that they are harmful to cells.
A new look at aggregates
In spite of earlier beliefs, could it be possible that aggregates serve some role in actually preventing the disease? Towards the end of 1998 a group of scientists from the Children's Hospital in Boston and Harvard Medical School published a bold paper suggesting that aggregates might not be nearly as pernicious as previously thought. Saudou and colleagues were able to partially inhibit the formation of aggregates by introducing a mutation in another protein important for aggregation, thus not affecting huntingtin itself. Without nearly as many nuclear aggregates, the researchers observed something amazing and unexpected: instead of subsiding, cellular death was accelerated.
In one paper the whole notion that aggregates were causing cellular death was thrown for a loop. Suddenly, the possibility existed that aggregates were actually one strategy for dealing with mutant huntingtin and that the mutant protein itself was at fault for cell death.
Soon after supporting research emerged from Xiao-Jiang Li's lab at Emory University. The group had developed a specific cell line from rats that could express the mutant huntingtin protein. Although they observed very few aggregates, the cells had abnormal morphologies and a high death rate.
A new line of thinking began to emerge in the world of HD research. Mutant huntingtin could affect cellular death by interfering with DNA or other important factors to turn off and on genes. If the huntingtin protein were more toxic in its soluble form where it could move freely around the nucleus and interact with other molecules, then inactivating huntingtin by forming insoluble aggregates would make perfect sense as a cellular coping strategy.
Of course this does not imply that aggregates are completely non-toxic. By virtue of their sheer size in the compact nucleus they could get in the way of various essential processes. However, their effect may be less toxic as road-blocking clumps than allowing soluble huntingtin to interact directly with DNA or other regulatory factors.
Two camps regarding aggregates
In light of this new evidence, the field of HD research has been divided into two camps. On one side are those that maintain that aggregates are the central cause of cellular death. Opposing them, others feel that aggregates are the result of a cellular coping strategy to deal with the mutation, which, they feel, is more lethal in its soluble, unclumped form.
One of the prominent scientists who believes that aggregates lead to cellular death is Max Perutz, most famous for originally describing the structure of hemoglobin. In a recent review article discussing the latest findings of various neurodegenerative disorders he argues that Saudou's bold paper missed one important point. Although Perutz concedes that no aggregates were seen, he believes that the researchers failed to account for the chain-like growth which precedes aggregation. He argues that this polymerization has the toxic effect—not soluble, individual huntingtin proteins.
Although no one can say for sure that they know the secret of aggregation, the field of research surrounding HD as well as other neurodegenerative disorders is exploding with new researchers and, in turn, new findings. In Dr. Li's lab at Emory, for example, there are numerous ongoing research projects to address the role of aggregation. One project uses yeast as a model system to see the toxic effects of aggregates while another focuses on the direct interaction between huntingtin and DNA.
Currently there is no known cure for Huntington's disease. With all of the current investigation, however, there is hope that in the next few years we may finally understand the importance—or unimportance—of HD aggregation and be able to apply that knowledge towards a treatment.
References:
- Davies SW, et al. (1997). Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90, 537-548.
- Li SH, Cheng AL, Li H, and Li XJ (1999). Cellular defects and altered gene expression in PC12 cells stably expressing mutant huntingtin. J. Neuroscience 19, 5159-5172.
- Perutz MF (1999). Glutamine repeats and neurodegenerative diseases: molecular aspects. Trends in Biochemical Sciences 24(2), 58-63.
- Saudou F, Finkbeiner S, Devys D, and Greenberg ME (1998). Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95, 55-66.
- Sisodia SS (1998). Nuclear inclusions in glutamine repeat disorders: are they pernicious, coincidental, or beneficial? Cell 95, 1-4.
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