BioWorld International Correspondent

PARIS - Biologists at two French medical research establishments discovered a new pathway for blocking neuron death in Huntington's chorea, one of a number of neurodegenerative diseases in which some neurons die without warning, impairing the proper function of the organism.

By studying how neurons die in that affliction, researchers at the French National Institute for Scientific Research (CNRS) and the National Institute for Health and Medical Research (INSERM) identified two agents that could prevent the death of the neurons and might become therapeutic targets for the treatment of the disease.

Huntington's chorea is caused by the mutation of the IT15 gene located on chromosome 4. It is a dominant autosomal genetic disease.

The function of the Huntingtin protein remains unknown, but in its normal state it contains repetitions of an amino acid called glutamin. If the repetitions exceed the threshold of about 35 to 40 glutamins, the protein is mutated and induces Huntington's disease. The more numerous the repetitions of glutamins, the earlier the symptoms of Huntington's appear.

A different region of the brain is targeted in each neurodegenerative disease caused by a similar type of genetic mutation inducing neuron death. In the case of Huntington's chorea, the phenomenon affects the neurons of the striatum, which is involved in the control of movement.

To identify the mechanisms by which the mutated Huntingtin protein induces neuron death, the CNRS and INSERM researchers developed a cellular model reproducing the characteristics of the disease. The model enabled them to show that the mutated Huntingtin protein must accumulate in the nucleus of cells to induce neuron death by apoptosis. The researchers showed that two proteins, IGF-1 (insulin growth factor-1) and Akt, have a neuroprotective effect, meaning they are able to block both neuron death and the formation of intranuclear aggregates in cells in which the Huntingtin protein is mutated.

The researchers also found that the Akt protein acts against the mutated Huntingtin protein. Once the Huntingtin protein is modified by Akt, no more aggregates are formed in the nucleus and death by apoptosis is impeded. That chemical transformation thus wipes out the negative effects on cells of the mutated Huntingtin protein.

The researchers' discovery marked the first time that factors acting directly against the protein involved in Huntington's chorea had been identified. They also discovered that the Akt protein takes an abnormal form in patients suffering from Huntington's, providing further proof of the Akt pathway's involvement in the disease.