More than a century after Huntington’s disease was clinically identified, there is still no cure available to the 250,000 Americans — or 6.2 million people worldwide — who suffer devastating mental, physical and emotional deterioration from the disease’s genetically programmed destruction of their brain cells.
Several medications offer limited relief from symptoms during the early stages of the disease, but they typically become ineffective against the increasingly severe incapacitation that occurs during the middle and late stages of the always-fatal malady.
This bleak prognosis was brightened recently by breakthroughs at Notre Dame’s Walther Cancer Research Center. A team of researchers headed by Crislyn D’Souza-Schorey, assistant professor of biological sciences, discovered that a selectively modified protein can potentially slow or even halt the otherwise relentless progression of Huntington’s disease.
Significantly, the protein works organically by exponentially increasing the brain’s natural defenses. This is in sharp contrast to other proposed treatments that rely either on potentially toxic drugs, which often cause severe side effects, or upon fetal stem-cell transplants, which are morally objectionable to many patients. The findings of D’Souza-Schorey’s research were published in the March 2002 edition of the science journal Nature Cell Biology.
Huntington’s disease is caused by a single mutant gene located on Chromosome 4. It is dominant, which guarantees that everyone who inherits the gene will contract the disease. It is also unlinked, which means individuals of both sexes and of all ethnic backgrounds are equally susceptible. The disease most often strikes between the ages of 30 and 45, but onset sometimes occurs as early as age 2. Children struck by the juvenile form rarely survive to adulthood. Each child of a Huntington-positive parent has a 50 percent chance of inheriting the fatal gene.
The mutant “huntingtin” gene produces corresponding mutations in the related huntingtin protein. Although the normal form of this protein is found throughout the body and is essential to life, the mutated form is toxic to cells in several key regions of the brain. It clumps together with another protein — Arfaptin2 — in brain cells. There is strong empirical evidence that these clumps disrupt brain activity, leading to diminished intellectual ability, memory loss, spastic twitching, and loss of balance and coordination.
Scientists had theorized that Arfaptin2 was the primary cause of the clumping. D’Souza-Schorey’s team confirmed, both at the molecular level and in genetically engineered mice, that the proteins do indeed cause clumping of the mutant huntingtin proteins and that they do so by deactivating proteosomes, specialized “decontaminating” enzymes that would otherwise destroy the defective proteins.
After establishing the mechanisms of clumping, the research team began searching for a substance that could prevent clumps from forming. Ironically, they discovered that the magic bullet is a selectively manipulated version of the same protein that causes the clumping. Removing one end of the normal protein — effectively reversing its biological function — creates the therapeutic variant. When these truncated proteins are introduced into diseased cells, they surround the clumps with ring-shaped walls and simultaneously restore the proteosome enzymes’ ability to destroy the defective huntingtin proteins.
D’Souza-Schorey emphasizes that it is too early to promise a cure for Huntington’s. She is certain, however, that her team’s work promises “exciting” new therapeutic and diagnostic strategies. It now seems probable that the selectively manipulated version of the clump-causing protein will be tested both in stand-alone form and in combination with existing drugs that prolong life and provide symptomatic relief but don’t control the build-up of huntingtin clumps in the brain.
Many prominent researchers are expressing cautious optimism that Alzheimer’s disease, Parkinson’s disease and cystic fibrosis — all of which are characterized by formation of aggregate clumps in the brain — might be treatable with a manipulated version of the clumping-causing protein.