Like a good parent, a protein called huntingtin helps to safeguard key nerve cells in the brain. When the huntingtin protein is defective, however, certain neurons can become damaged, resulting in Huntington's Disease, a debilitating and fatal form of brain degeneration characterized by physical, mental and emotional disturbances.
The discovery of one of normal huntingtin's exact functions within the brain--to be published online by the journal, Science, as part of the Science Express web site on 14 June--suggests novel therapeutic strategies to fight the disorder.
"Much additional research must be completed before these findings can help patients, and we want to be clear that this is not a cure," researcher Elena Cattaneo of the University of Milan emphasized. "But, we're optimistic that our work will help guide the development of new therapies, such as drugs to replace or boost the activity of normal huntingtin, or to increase levels of another brain protein, BDNF."
Cattaneo's research was supported mainly by Telethon Italy, and by the Huntington's Disease Society of America, two non-profit organizations.
A primarily hereditary disorder of the central nervous system, the prevalence of Huntington's Disease ranges from one in every 10,000 individuals in Europe and the United States, to seven of every 1,000 in Venezuela, said Cattaneo, who directed the international Science study team. In Italy, an estimated 4,000 individuals are affected, and another 12,000 carry the disease gene but have not yet developed symptoms.
Symptoms range from uncontrollable muscular movements to memory lapses, difficulty with swallowing, and behavioral or psychological changes. Striking most often in mid-adulthood, between ages 30 and 50, the disease progresses toward death within 15 to 20 years.
Huntington's Disease has been traced to a defective gene on chromosome 4, which produces the huntingtin protein, discovered in 1993. Previous research has shown that the mutation of huntingtin launches the protein into overdrive, a state described by scientists as a toxic "gain-of function," resulting in neuronal cell death.
While the hyperactivity of mutant huntingtin may account for some aspects of the disease, Cattaneo's team has revealed, it's largely the loss of "good parenting," through the mutation of huntingtin, that leaves neurons vulnerable to damage. Huntingtin's normal function, researchers show, is to regulate the transcription of the BDNF protein, which is essential for the survival of neurons located within the striatum. This transcription is impaired with mutant huntingtin, resulting in lowered levels of neuron-protecting BDNF.
"We believe that the loss of huntingtin's beneficial functions contributes to the disease," said Cattaneo.
Researchers examined normal huntingtin's function in cultured cells and laboratory animals. First, they produced striatal cells that expressed either normal or mutant huntingtin. Then, they measured the cells' production of certain biochemicals, called neurotrophins, which help neurons survive. Cells expressing normal huntingtin had high levels of the neurotrophin, BDNF, whereas this effect was lost in cells expressing the mutant protein.
To survive, adult neurons in the brain's striatum must receive BDNF produced within the cerebral cortex. In transgenic mice expressing normal huntingtin, Cattaneo reported, BDNF proceeded via the usual pathway, from the cortex to the striatum. But, this delivery system was disturbed in mice expressing mutant huntingtin, as less BDNF was generated in the cortex. These findings were further confirmed by dose-dependent tests, and by the post-mortem analysis of a human brain afflicted by Huntington's Disease: Evidence of reduced BDNF transcription was found in the cortex, with subsequently reduced levels of the neurotrophin in the striatum.
Cattaneo speculates that similar "loss-of-function" mechanisms may play a role in seven other neurodegenerative diseases.
Efforts to treat Huntington's Disease have so far ranged from experimental fetal-cell transplants to neuron-protecting agents and antipsychotic or antidepressant medications. Other strategies include, for example, the use of an antibiotic that blocks the production of two enzymes known to fragment mutant huntingtin, producing toxic effects in cells.
"There will be no drug ready tomorrow, based on this research," Cattaneo said. "But, now we have a new idea for how to develop therapies, perhaps in the very close future. Before treatments can be proposed, we need to understand exactly how huntingtin speaks to the BDNF gene to increase its activity. We believe this research will progress very rapidly over the next few months. As a next step, trials are under development to deliver BDNF via gene therapy to HD transgenic mice."
With Cattaneo, authors on the Science paper include Chiara Zuccato, Andrea Ciammola, Dorotea Rigamonti, Donato Goffredo, Luciano Conti, Simonetta Sipione, and Vincenzo Silani, all of the University of Milan; as well as Blair R. Leavitt and Michael R. Hayden of the University of British Columbia; Marcy E. MacDonald of Massachusetts General Hospital; Robert M. Friedlander of Brigham and Women's Hospital; and Tonis Timmusk of the Institute of Biotechnology in Finland. [Zuccato et al., "Loss of Huntingtin-Mediated BDNF Gene Transcription in Huntington's Disease."]
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