HD Lighthouse Contributing Editor's Comment: Dr. Brusilow presents the intriguing idea that the polyglutamine expansion that causes HD may be an evolutionary 'experiment' to preserve brain function during periods of malnutrition.

I've wondered about this myself. The huntingtin's protein is an old one -- even yeast have it -- yet, humans are the only animal to get Huntington's Disease. Primates don't develop the disease (unless it's genetically engineered). He notes that human beings seem prone to polyglutamine expansions. There are nine diseases associated with these expansions but there are also other expansions in genes which do not appear to cause any disease. Why us? Does polyglutamine expansion give our species any advantage? It is known that people with the HD gene are less likely to get certain forms of cancer, most likely because of elevated levels of P53 a protein which suppresses cancer. But is there anything else?

Brusilow notes that the more advanced animals have more polyglutamine (CAG) repeats in the N-terminal region of the huntingtin's protein (where extra repeats in people cause HD). Fruitflies don't have any, zebrafish have four, mice 7-8, primates 9-16 and humans average around 20 to 30. The N-terminal region also has repeats that code for proline, another amino acid.

Glutamate is the metabolic product of glutamine and proline. Both glutamine and glutamate are present in the brain in high concentrations, the highest of all the organic compounds. Glutamate is an extremely important neurotransmitter which rapidly conveys information from our senses as well as motor commands from neuron to neuron. It's also involved in memory and learning and energy metabolism.

There's a glutamine-glutamate cycle where glutamine is converted to glutamate in the neurons while glutamate is converted to glutamine in the astrocytes (a type of glial cell which supports the neurons). It's very important that the glutamate released during neurotransmission be taken right back to the astrocytes because too much extracellular glutamate is toxic. The excitotoxicity theory of neurodegeneration in HD and other diseases is that too much glutamate can overstimulate receptors and allow too much calcium into the cell which in turn releases enzymes which damage various cell components.

Too much glutamine can be toxic too. High concentrations of glutamine are needed to produce glutamate but too much would cause osmotic stress and cause the brain to swell.

As important as glutamate is and despite the necessity for the brain to maintain high concentrations of glutamine to produce it, there's clearly a delicate balance to be maintained. Brusilow speculates that the N-terminal region of the huntingtin protein which is is broken down and recycled during protein turnover represents a 'safe' reservoir of glutamine and proline which can be called upon when needed during times of famine when malnutrition may reduce glutamine levels.

-- Marsha L. Miller, Ph.D.
Posted to the HDL: 30 Jul 2006

Is Huntington's a Glutamine Storage Disease?

Huntington's disease is a neurological disorder caused by the expansion of a polyglutamine tract in the protein huntingtin. Several other neurological diseases also result from the expansion of polyglutamine regions in different proteins. Despite intense efforts, no definitive biochemical or physiological role for huntingtin has been described, nor has a function been assigned to the polyglutamine region in unaffected individuals. This article presents the hypothesis that polyglutamine expansions within huntingtin and other polyglutamine proteins provide a function in and of themselves. Incorporating multiple glutamine residues into a protein during synthesis, and releasing them during protein turnover, may represent a means of minimizing interruptions in brain levels of glutamine and glutamate during periods of malnutrition. The number and variety of different proteins containing polyglutamine expansions can be interpreted as a series of evolutionary "experiments" toward a nontoxic form for glutamine storage. # # #

Source: The Neuroscientist 2006 Aug;12(4):300-4.

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