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Therapeutics for Huntington's and Related Diseases Could Pack a One-Two Punch

For release: Tuesday, June 5, 2007

Added to its devastating neurological symptoms, Huntington's disease (HD) carries with it a lesser-known horror.  The genetic mutation that causes the disease can grow larger, causing its symptoms – involuntary movements, dementia, and dramatic personality changes – to grow worse across generations and even during a single lifetime.  New research sheds light on how the mutation grows and offers hope for locking it down.

The mutation behind HD is known as a trinucleotide repeat expansion.  It's a stutter in the genetic code that – in the language of DNA – is made up entirely of a single repeating three-letter phrase.  While such repeats are normal and occur in many genes, an expanded stretch of them can be disastrous.  Trinucleotide repeat expansions in different genes are responsible for dozens of neurological and neurodegenerative diseases, including HD and several spinocerebellar ataxias (SCA's).

Scientists know more about how the repeat expansions cause disease than about how the expansions grow.  Nancy Bonini, Ph.D., a biology professor at the University of Pennsylvania in Philadelphia, has found evidence that, for a subset of trinucleotide repeat diseases including HD, the two processes may be connected, each feeding off the other.

The upshot is that "a single therapeutic for these diseases could have multiple benefits," said Dr. Bonini, who is supported by the National Institute of Neurological Disorders and Stroke (NINDS).

Why are repeat expansions harmful?  In HD, several SCA's and other diseases, the expansions are embedded in a part of DNA that will serve as a template for making protein.  This leads to a protein with an abnormally long stretch of the amino acid glutamine.  Proteins with abnormally long polyglutamine—polyQ in molecular biologist’s shorthand—are not only defective, they’re considered toxic. They build up inside cells, forming garbage heaps where other normal proteins become trapped and unable to carry out their vital functions.

At the DNA level, trinucleotide repeats are unstable.  In a person who has HD or another such repeat disease, although the repeats can shrink, they tend to expand – and longer repeat expansions are generally associated with more severe disease.  Growth of the repeats within a person's sperm or ova can cause "anticipation" – an earlier onset and faster progression of disease in children who inherit the mutation.  In animal models for these diseases, the repeats can also grow within brain cells, potentially accelerating the cells' demise.

Experimental compounds have shown promise in animal models for reducing the harmful effects of polyQ, and it's possible that the same drugs could curb further growth of the expansions, Dr. Bonini said.

Dr. Bonini studies trinucleotide repeat diseases in the fruit fly – an animal model prized for its big bag of genetic tricks.  She and others have shown that when the repeat expansions that cause diseases like HD or SCA are inserted into the flies' genome and targeted to their brain cells, the flies develop a neurodegenerative disease.  In work published in Science,* she and Joonil Jung, Ph.D., a postdoctoral fellow in her lab, targeted these expansions to the flies' germ cells (sperm and ova).  They found that, just as in humans, the expansions tended to grow longer in the flies' offspring.

Other genetic experiments enabled them to examine the mechanisms for this growth.  In one set of experiments, they found that a cell's normal system for repairing DNA appears to stimulate repeat growth.  This fits with a recent NIH-funded study on mice with HD.

They also discovered they could stimulate the repeats to grow longer in flies by genetically knocking down CBP – a protein that regulates gene activity.  CBP is one of the proteins ensnared by polyQ, and many scientists believe that its depletion explains why polyQ is toxic.  The result in flies means that CBP could play an even more significant role that previously thought.  It could link polyQ toxicity and repeat instability together in a vicious cycle – where the repeats lead to the formation of polyQ protein, the polyQ protein sequesters CBP, the loss of CBP makes the repeats grow, and the process loops back on itself.

"This means that a drug that reduces polyQ toxicity could also help clamp down on repeat instability," Dr. Bonini said.

Preliminary experiments support her idea.  A class of candidate drugs, known as HDAC inhibitors, has been shown to compensate for the loss of CBP and protect against neurodegeneration in animal models of polyQ disease.  When she and Dr. Jung tested one of these compounds in their fly model, they found that it curbed the growth of repeats from one generation to the next.

The safety and tolerability of HDAC inhibitors is currently being evaluated in HD patients.

*Jung J and Bonini N, "CREB-Binding Protein Modulates Repeat Instability in a Drosophila Model for PolyQ Disease."  Science, March 30, 2007, Vol. 315, pp. 1857-1859.

-By Daniel Stimson, Ph.D.

Last Modified June 5, 2007