Scientists Find How Gene Leads to Huntington’s

Four years after the discovery of the defective gene that causes Huntington’s disease, researchers have produced the first clues about how the gene causes the devastating disorder.

That new insight, experts say, could quickly lead to the first successful treatments not only for Huntington’s, but also for half a dozen other diseases that have an identical genetic defect.

An estimated 60,000 Americans suffer from the diseases--all of which interfere with the ability to walk and move and are eventually fatal--and perhaps twice that many carry one of the genes and will eventually develop symptoms.

Although each disease can be traced to a different gene, each gene shares the same defect--a genetic “stutter” that inserts from 30 to 150 copies of the amino acid glutamine into key proteins, altering their properties and causing the disease.

New studies in mice, reported today in the journals Cell and Neuron, indicate that these glutamine-rich regions cause the proteins to clump together over time until they reach a critical mass that triggers their migration into the nucleus of brain cells, where they kill the cells.

Researchers are already looking for drugs that can prevent the proteins from forming masses and thereby delay the onset of symptoms.

“This is the most exciting thing that has happened since the discovery of the gene [for Huntington’s] and a major step forward toward finding the cure,” said Nancy Wexler, president of the Hereditary Disease Foundation. “It’s just incredibly exciting.”

The findings are “quite extraordinary,” added UCLA neuroscientist Allan J. Tobin. “The results say, yes, there is a single mechanism that underlies the neuropathology in all of these diseases. All depend on the movement of some fragment of protein into the nucleus.”

Furthermore, he said, the findings give researchers a valuable tool to test potential drugs for the treatment of Huntington’s and the other diseases. “We’re all pretty high about this,” he added.

Huntington’s is characterized by jerky, involuntary movements called chorea, loss of control of bodily functions, and dementia, a progressive deterioration of memory and thought processes.

The identification of the Huntington’s gene by an international team in 1993 after 10 years of intensive work touched off a wave of anticipation that a treatment might be imminent. But that excitement soon turned to frustration, as researchers struggled to isolate the protein produced by the gene and figure out exactly what the protein does.

They still do not know the protein’s normal function. But they do know it is crucial to life: Mice grown from fertilized eggs in which the protein is deleted die while still embryos.

“It’s clear that we can live with the abnormal protein, so it is probably doing something horrible in addition to its normal function,” Wexler said.

The gene abnormality in Huntington’s was the first of its type to be found. The healthy gene contains a segment in which three nucleotides--the building blocks of genes--called C, A and G, are repeated as many as 38 times. That, in turn, instructs the cell’s protein-building machinery to incorporate the amino acid glutamine into the protein as many as 38 times in a row.

In the defective gene, the CAG segment is repeated from 40 to 150 times. Researchers quickly found that the more often the segment is repeated, the earlier in life the disease strikes and the more serious it becomes.

Scientists have since discovered several other diseases with the same defect: spinal and bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, and spinocerebellar ataxia types 1, 2, 3, 6 and 7. All are characterized by the death of brain cells in specific regions and movement disorders that eventually lead to death.

All also show a phenomenon that researchers call “anticipation.” When the disease is passed from parent to child, the number of segment repeats is increased.

Dr. Huda Y. Zoghbi of the Baylor College of Medicine describes a Houston family in which spinocerebellar ataxia type 1 has passed through seven generations. The first family member to have it lived well past 80 and suffered only minor impairments. By the sixth generation, family members were dying in their 30s and 40s. In the seventh and current generation, it strikes before adulthood and two children, ages 9 and 15, have already died.

The key to the new discoveries was provided by geneticist Gillian Bates of Guy’s Hospital in London, who was trying to understand why the defective gene grows from generation to generation. She inserted a segment of the human gene containing more than 115 CAG repeats into mice and found that, to everyone’s surprise, they developed the disease.

Working with Dr. Stephen W. Davies and his colleagues at University College London and geneticists Hans Lehrach and Erich Wanker at the Max Planck Institute for Molecular Genetics in Berlin, Bates began tracking the fate of proteins produced in mice by the human gene. Starting with a large group born at the same time, she would kill one or two each day and determine where the protein was found in the brain.

She saw that the protein stayed in the cytoplasm--the portion of brain cells outside the nucleus--early in life, while the mice were still healthy. As the mice aged, however, the proteins were attracted to each other and formed balls. When the clumps reached a certain size, they mysteriously migrated into the cells’ nuclei. At that point, the cells began dying and symptoms began to occur.

In a separate paper in the journal Neuron, pharmacologists Henry L. Paulson of the University of Iowa, Randall N. Pittman of the University of Pennsylvania and their colleagues report similar results with Machado-Joseph disease, also known as spinocerebellar ataxia type 3.

“It’s a pathological hallmark that suggests that a single disease mechanism may underlie this whole group of afflictions,” Pittman said.

Researchers are confident that the mouse results can be extrapolated to humans. Researchers at Columbia-Presbyterian Hospital in New York City reported in 1978 that biopsies of brain tissue from living Huntington’s patients showed aggregates virtually identical to those observed in mice by Bates. But people were uncomfortable with the idea of taking brain tissue from living patients, “and nobody wanted to repeat the study,” Tobin said.

Apparently, the aggregates break down quickly after death and are difficult to find during an autopsy. But researchers are now looking for them in humans and beginning to find traces, he said.

Meanwhile, chemists are screening drugs in the test tube and in the mice to find those that will block the aggregation and perhaps delay or prevent the disease. Depending on what they find, tests in humans could begin within a couple of years.

(BEGIN TEXT OF INFOBOX / INFOGRAPHIC)

Excess Amino Acid Linked to Diseases

Researchers have discovered how a defective gene causes Huntington’s disease. It appears that the same mechanism operates in several other neural disorders that have a similar defect, which involves an unusual number of glutamines in a key protein.

Disease: Huntington’s

Defective Protein: Huntington

Glutamines

Normal: 11-34

Mutant: 37-121

Neural Regions Affected: Basal ganglia, cerebral cortex

*

Disease: Spino muscular atrophy (Kennedy’s disease)

Defective Protein: Androgen receptor

Glutamines

Normal: 11-33

Mutant: 40-62

Neural Regions Affected: Spinal cord, brain stem, sensory neurons

*

Disease: DRPLA (dentatorubral-pallidoluysian atrophy)

Defective Protein: Atrophin

Glutamines

Normal: 7-23

Mutant: 49-75

Neural Regions Affected: Cerebellum, brain stem, basal ganglia, spinal cord, cerebral cortex

*

Disease: Spinocerebellar ataxia, type 1

Defective Protein: Ataxin-1

Glutamines

Normal: 6-44

Mutant: 40-82

Neural Regions Affected: Cerebellum, spino-cerebellar system, inferior olive

*

Disease: Spinocerebellar ataxia, type 3

Defective Protein: MJD I

Glutamines

Normal: 13-40

Mutant: 68-79

Neural Regions Affected: Multiple motor control regions of brain and spinal cord

Source: Science