The neurons that die off in Huntington's disease sufferers are done in by a genetic mutation that turns a good protein bad. But a new study suggests it's not just the presence of the mutant that kills the neurons--a deficit of the normal protein also plays a key role. Hot on its heels, another study implicates low levels of the same protein in a range of other brain disorders, offering hope for broadly effective neurological treatments.
In Huntington's disease, neurons slowly waste away. The neurons die because mutations warp a harmless protein called Huntingtin into a toxic form. Most researchers have eyed the mutant protein, which seems to cause trouble by aggregating into lumps within neurons. A missing part of the puzzle has been the function of the Huntingtin protein in healthy people and how its loss might contribute to the disease. A team led by Elena Cattaneo, a neurobiologist at the University of Milan, Italy, has focused on BDNF, a molecule required for the survival of the subset of neurons that die off in Huntington's patients. They showed 2 years ago that normal Huntingtin protein helps protect these neurons by somehow boosting BDNF production (Science, 20 July 2001, p. 493).
This week, Cattaneo and colleagues explain how Huntingtin makes the connection. Rather than directly pumping up BDNF, Huntingtin puts the brakes on REST/NRSF, a protein that blocks the expression of not only BDNF but several other neuron-specific genes. A crucial job of healthy Huntingtin seems to be to sequester REST/NRSF in the cytoplasm; mutated Huntingtin fails to bind REST/NRSF, allowing it to migrate into the nucleus and sabotage neurons, the team reports in the 27 July Nature Genetics. Potentially, Huntington's disease could be treated with drugs that block REST/NRSF from entering the nucleus, Cattaneo suggests.
And such drugs may prove useful for more than just Huntington's. Robert Friendlander, a neurobiologist at Harvard University, and colleagues report online this week in the Journal of Neurochemistry that Huntingtin protein is depleted in a variety of brain disorders that do not involve mutation, such as after brain trauma, stroke, and spinal cord injury. So finding a way to treat one of these could eventually open the door to treatments for the rest.
The work excites Marc Peschanski, a neurobiologist at the French national institute of medical research, INSERM, in Creteil, France, because the idea that Huntington's disease is caused solely and directly by the mutant protein "has remained basically unchallenged for decades." Peschanski says treatments are still a long way off, but this work should "help widen the possibilities" for drug research.