Polyglutamine Diseases: A Devastating Genetic Stutter
By Laura Bonetta

Like a tiny time bomb, a genetic mutation can remain silent for many years before striking suddenly. Consider the mutation that causes the neurological disease spinocerebellar ataxia type 1 (SCA1). A person with this mutation in his or her DNA will usually be healthy until about 20 to 40 years of age and then will start having problems with balance and speech and perhaps lose muscle strength in the arms and legs. While the symptoms are barely noticeable at first, they progressively worsen, and typically the person dies from breathing difficulties within 20 years.

In 1993, HHMI investigator Huda Y. Zoghbi and collaborator Harry T. Orr discovered the gene that causes SCA1 when mutated. The disease-causing mutation is a kind of genetic stutter: a sequence of three nucleotide bases (cytosine-adenine-guanine, or CAG) that is repeated many times within the gene’s sequence. Normal individuals have between 6 and 44 copies of the CAG repeat in both alleles of their SCA1 gene. When the number of CAG repeats exceeds 20, the repeat tract is interrupted by one to three copies of the nucleotide sequence CAT—that is, the CAG repeats in the tract are not contiguous. In a person with SCA1, on the other hand, one of the alleles has anywhere from 39 to 82 contiguous CAG repeats. The repeated sequence inside the SCA1 gene has expanded and is not interrupted by CAT.

A person with a SCA1 gene containing the expanded repeat has a 50 percent chance of passing the faulty gene to each of his or her children. If a child inherits the mutant gene, he or she will develop the disease eventually. There’s an important twist to this sad story. The number of CAG repeats inside the SCA1 gene typically increases as the mutant gene is transmitted from parent to child. As the number of repeats increases with each generation, those who inherit the mutant gene develop symptoms earlier in life, and the symptoms are more severe.

Trinucleotide Repeat Diseases

SCA1 is just one example of a class of genetic diseases caused by dynamic mutations involving the expansion of triplet sequence repeats. In reference to this common mechanism, these disorders are called trinucleotide repeat diseases. At least 14 such diseases are known to affect human beings. Nine of them, including SCA1 and Huntington disease, have CAG as the repeated sequence (see table). Since CAG codes for an amino acid called glutamine, these nine trinucleotide repeat disorders are collectively known as polyglutamine diseases.

Although the genes involved in different polyglutamine diseases have little in common, the disorders they cause follow a strikingly similar course. Each disease is characterized by a progressive degeneration of a distinct group of nerve cells. The major symptoms of these diseases are similar, although not identical, and usually affect people in midlife. Given the similarities in symptoms, the polyglutamine diseases are hypothesized to progress via common cellular mechanisms. In recent years, scientists have made great strides in unraveling what the mechanisms are.

Toxic Glutamine Tracts

Above a certain threshold, the greater the number of glutamine repeats in a protein, the earlier the onset of disease and the more severe the symptoms. This suggests that abnormally long glutamine tracts render their host protein toxic to nerve cells.

To test this hypothesis, scientists have generated genetically engineered mice expressing proteins with long polyglutamine tracts. Regardless of whether the mice express full-length proteins or only those portions of the proteins containing the polyglutamine tracts, they develop symptoms of polyglutamine diseases. This suggests that a long polyglutamine tract by itself is damaging to cells and does not have to be part of a functional protein to cause its damage.

Nevertheless, the particular protein containing the polyglutamine tract does appear to play a role in determining the specific symptoms of disease. Although all proteins known to have expanded polyglutamine repeats are expressed in many tissues in the human body, each is damaging only to a specific group of nerve cells. The nerve cells that are affected differ from one disease to the next. For example, the protein product of the SCA1 gene is ataxin-1, a protein that is normally produced in large amounts in Purkinje cells, the neurons responsible for coordination of movement. These neurons are the ones that start to degenerate first in people with SCA1.

How do polyglutamine tracts cause a malfunction and, ultimately, the death of nerve cells? A clue for answering this question comes from the observation that patients with polyglutamine diseases have protein deposits inside some of their nerve cells. These so-called neuronal inclusions contain not only the mutant polyglutamine proteins but also other proteins.

Changes in Protein Folding and Degradation

A protein is produced to perform a specific function inside a cell. Once that is accomplished, the protein is no longer needed and is quickly removed by a proteasome—a complex of proteins within the cell that destroys unwanted proteins. The proteasome “knows” which proteins to destroy because they are marked by a chemical tag called ubiquitin.

Ubiquitin-tagged ataxin-1 and other proteins with expanded polyglutamine tracts have been found inside neuronal inclusions. It seems that the cell had marked these mutant proteins for destruction, but they proved resistant to attack. Because these proteins cannot be removed by the cell with the usual efficiency, they accumulate—the longer the polyglutamine tracts, the more resistant the proteins and the faster they accumulate.

The expanded polyglutamine tract may render a protein more resilient because the abnormally long string of glutamines prevents the protein from folding into its proper shape. Normally, the cell uses a special set of proteins, called chaperones, to “fix” proteins that are not folded properly. Chaperones are present in neuronal inclusions, suggesting that the cell has recognized the mutant polyglutamine-containing proteins as errors and tried hard to fix them. For decades, the normal levels of chaperones may be sufficient to fix these errors, but eventually the cell loses the fight. Indeed, scientists have been able to reduce the toxic effects of expanded polyglutamine proteins and delay the start of disease in mouse models of polyglutamine diseases by boosting the levels of chaperones inside nerve cells.

Changes in Cell Functions

How does the accumulation of proteins with expanded glutamine repeats result in cell damage? Part of the answer may be that as the mutant proteins accumulate and form protein clumps inside the cell, they recruit other proteins, keeping them from performing needed functions.

For example, scientists think that the symptoms of SCA1 are not directly caused by the loss of normal ataxin-1 function but rather by the interaction between ataxin-1 and another protein called LANP. LANP is needed for nerve cells to communicate with one another and thus for their survival. When the mutant ataxin-1 protein accumulates inside nerve cells, it “traps” the LANP protein, interfering with its normal function. After a while, the absence of LANP function appears to cause nerve cells to malfunction.

Many transcription factors—proteins that control the expression of other genes—have also been found in neuronal inclusions in different diseases. It is possible that these transcription factors interact with the polyglutamine-containing proteins and then become trapped in the neuronal inclusions. This in turn might keep the transcription factors from turning genes on and off as needed by the cell. The common disease mechanism for polyglutamine diseases may be a sort of gumming up of the cellular machinery, hampering the activity of many genes and eventually leading to the catastrophic failure of cellular systems and death.

The Road Ahead

Scientists are just now starting to understand how the mutations in polyglutamine diseases affect the production and destruction of proteins and the interactions among proteins. A clearer understanding of these processes should have important consequences for not one disease but several. In SCA1, for example, finding a way to stop mutant ataxin-1 from accumulating may help scientists find a treatment for all polyglutamine diseases and perhaps other diseases, such as Alzheimer and Parkinson, that involve protein deposits inside cells.

Summary of Polyglutamine Diseases

Sources: C.J. Cummings and H.Y. Zoghbi, Trinucleotide repeats: Mechanisms and pathophysiology, Annual Review of Genomics and Human Genetics 1 (2000): 281–328; K. Nakamura, S.Y. Jeong, T. Uchihara, M. Anno, K. Nagashima, T. Nagashima, S. Ikeda, S. Tsuji, and I. Kanazawa, SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein, Human Molecular Genetics 10 (2001): 1441–48.

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