Alzheimer's disease has its telltale amyloid plaques; Parkinson's, itslost dopamine-secreting neurons; multiple sclerosis, motor neuronsstripped of their myelin sheaths.

What does Huntington's disease have in the way of clues to causeand cure? Precious little _ although that little is growing, and it isprecious.

After physician George Huntington described his namesake diseasein 1872, it took just over a century for molecular biologist JamesGusella at Massachusetts General Hospital to pin down theHuntington's gene's location to human chromosome 4, in 1983. Itthen took another decade before Gusella could actually clone it, in1993.

What purpose that gene serves, in sickness and in health, is still amystery, which research groups in many countries are striving tosolve. They now realize that the Huntington's gene carries anunhealthy load of triplet repeats. These are a trio of nucleotides _cytosine, adenosine and guanine (CAG) _ which encode the aminoacid, glutamine.

The problem is that they encode it over and over and over again _more than 36 CAG repeats in the Huntington's gene. (See BioWorldToday, Aug. 2, 1994, p. 1.) Normal individuals can harbor thatburden of junk DNA up to 35 CAG iterations without ill effect.

In Huntington's disease sufferers, those ill effects are physically,mentally, genetically and socially horrendous: Huntington's begins toafflict its victims, men and women in the prime of life, around age 40,and progresses inexorably, untreatably, to death 10 or 15 years later.

Symptoms may start, insidiously, with peculiar muscle spasms ortwitches of face and limbs, non-stop during every waking hour. Fromtrivial nervous tics to bizarre involuntary movements to uncontrolledflailings and lashings about, they worsen until total incapacitationsets in.

Meanwhile, initial spells of irritability, moodiness, restlessness andlassitude magnify into full blown delusional and paranoid behavior,as the intellect deteriorates into dementia.

Huntington's _ The Hidden Horror

What makes these grotesque manifestations so pitiless is their geneticunderpinning: True to Mendelian inheritance rules, the child of anHuntington's parent has a 50-50 chance of being born with thedisease. But as its onset is deferred for 40 or so years, he or she won'tknow whether to contemplate marrying and starting a family, free ofthe dread uncertainty that the Huntington's time-bomb may explodeonly after child-bearing years are past.

About 30,000 Americans suffer from Huntington's disease, whichaffects about one in 10,000 individuals; 150,000 are at risk. (SeeBioWorld Today, March 2, 1993, p. 1.)

Mice don't manifest Huntington's, but their genome does include agene analogous to the human one. A group headed by medicalgeneticist Michael Hayden at the University of British Columbia,Vancouver, sequenced and characterized this murine version of theHuntington's gene in 1994. They found that it shared 90 percentsequence identity with Gusella's human version.

Then, to explore the function of this Huntington's-specific rodent DNA, the Canadians created a race of knockout mice,bereft of one Huntington's equivalent mutant gene. What theylearned appears in the current issue of Cell, dated June 2, titled,"Targeted disruption of the Huntington's disease gene results inembryonic lethality and behavioral and morphological changes inheterozygotes."

Geneticist Jamal Nasir is first author of this paper, and coordinator ofthe Huntington's gene project at the university. "Making geneknockouts," he told BioWorld Today, "is the classical and mostobvious approach for a geneticist. If you don't know what somethingdoes, you perturb it, you make mutations, and see what happens inthe absence of the protein the gene encodes."

He continued: "When we knocked out that murine gene, our findingturned out to be extremely intriguing. There were some aspects of ourgene-disrupted mice that appeared to share similarities with what wehad seen in Huntington's disease."

The team inserted its gene-ablating construct into the fertilized eggsof normal mice, implanted these in surrogate mothers, and raised up asecond-generation colony consisting of both heterozygous knockoutsand intact wild-type animals.

But embryos that received a double dose of the altered Huntington'sgene never made it to birth. These homozygotes died stillborn earlyin gestation, which proved to the researchers that the intact geneplays a crucial role in growth and development.

Testing The Life And Death Of Brain Cells

"When we set out," Nasir emphasized, "we weren't deliberatelytrying to create an animal model for the human Huntington's gene.Rather, we were trying to find out what the function of theHuntington's gene is, for the reason that it might eventually provideus with a clue in terms of prevention, therapy and drug discovery."

He and his team assumed that absence of that gene would affect thelife and death of certain brain neurons related to Huntington'sphysical and mental symptomatology. This called for testing thebehavior of the heterozygous knockout mice, compared to theirnormal controls, and examining the neuropathological state of theirrelevant brain tissues.

Since 1981, researchers have had at hand a gamut of mouse-levelgames for testing murine memory, cognition, dexterity and otheraccomplishments. (See BioWorld Today, June 6, 1995, p. 1.)

Putting their knockouts through these paces alongside controlsrevealed many similarities but some telling differences. Twoexamples:

* Mutant mice displayed two to four times more motor activity thancontrols, "suggesting that they habituate more slowly to the stimulusof a novel environment."

* In a test of remembering the former location of a hidden underwaterplatform, heterozygotes reflected "a deficit in cognitive flexibility, inwhich a previously successful strategy must be inhibited to develop anew strategy that is appropriate for a change in the demands of thetask. Mutant mice appeared to be incapable of making this strategyswitch."

"It is noteworthy that behavioral differences seen in [mutant] micerelative to controls," Nasir wrote in Cell, "are similar to those seen inrodents with lesions to the basal ganglia."

In one of the basal ganglia's five nuclei, the subthalamic nucleus, theVancouver team found that knockouts had 45 percent fewer neuronsthan controls. "This specific region of the brain," Nasir emphasized,"has generally been overlooked by scientists, who for many yearshave believed Huntington's primary site to be the striatum nigra. Soour new discovery raises the exciting possibility that the basal gangliais very important in the development of Huntington's disease." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.