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Neurology/Neuroscience Article Date: 07 Feb 2006 - 4:00am (UK) At the Institut Curie, CNRS and Inserm researchers have shown that Huntington's disease may be treated using the drug FK506, which is also used clinically to prevent graft rejection. Like Alzheimer's and Parkinson's, Huntington's disease is characterized by the abnormal death of neurons. The Institut Curie researchers have discovered that FK506 blocks the toxicity of the protein huntingtin, which causes the death of certain neurons leading to disease onset. FK506 is already used in a clinical setting and so is a candidate for fast-track development as a treatment for Huntington's disease. This study was published in the February 1, 2006 issue of The Journal of Neuroscience. Huntington's disease is a genetic disorder which affects approximately 6 000 people in France and is of concern to over 12 000 carriers of the mutated gene as yet untouched by clinical signs. It is characterized by uncontrolled movements, personality changes, dementia and death 10 to 20 years after onset of the first symptoms (see "Additional information"). Huntington's disease results from changes in the IT15 gene, which encodes a protein, huntingtin, whose function is incompletely elucidated. Normal huntingtin contains repeats of the amino acid glutamine, but mutant huntingtin contains more than 35 to 40 glutamines and induces the disease. Symptoms occur earlier as the number of repeats increases. This abnormal expansion of the polyglutamine tract in huntingtin results in structural changes, and the mutant huntingtin accumulates in neurons thereby causing their dysfunction and ultimately their death. The same type of mutation causes other neurodegenerative diseases, each involving different regions of the brain. In Huntington's disease, degeneration occurs in the neurons of the striatum, which are involved in the control of movement. Raúl Pardo and Emilie Colin at the Institut Curie are studying the mechanisms that lead to neuron death in Huntington's disease, under the direction of Frédéric Saudou and Sandrine Humbert(1). They have now shown that calcineurin, a protein abundant in the brain, chemically alters mutant huntingtin, which becomes more toxic for neurons. They have also discovered that by inhibiting calcineurin, FK506 "corrects" this chemical alteration in mutant huntingtin both in cultured neurons and in an animal model of the disease. FK506 even prevents the death of the striatal neurons. So, FK506 negates the harmful effects of mutant huntingtin in neurons. FK506 is already used therapeutically to prevent graft rejection, and so may be a candidate for fast-track development as a treatment for Huntington's disease. When apoptosis goes awry... In all organisms, cells grow, reproduce and then die. But their death occurs in various ways. They may die accidentally - necrosis - or "decide" to die - apoptosis, or programmed death. Apoptosis removes superfluous cells and rids the body of potentially harmful damaged cells. The least anomaly in apoptosis may result in dysfunction, leading to a variety of diseases: -- when apoptosis is blocked, damaged cells are no longer eliminated and so there is a risk of cancer. -- when programmed cell death is accelerated, there is abnormal loss of neurons, leading to certain neurodegenerative disorders, such as Alzheimer's, Parkinson's, and Huntington's diseases. Huntington's Disease Huntington's disease, also known as Huntington's chorea, is a rare neurological disorder affecting one person in 10,000 whose onset occurs between the ages of 35 and 50. The most striking symptoms are involuntary and abnormal saccadic movements of the limbs, head and neck (chorea). There are also mental disorders (anxiety, irritability, depression) and intellectual deterioration progressing to dementia. Death due to complications (pulmonary embolism, pneumonia, or other infection) occurs 15 to 20 years after disease onset. Clinical diagnosis is often difficult and time-consuming because of the highly variable symptoms that are easily confused with those of psychotic disorders. Diagnosis must be confirmed by magnetic resonance imaging of the brain and genetic testing. When there is a family history of the disease, predictive genetic testing is possible but should be considered carefully since the first symptoms appear relatively late in life and, at present, there are no treatments to delay onset or slow progression of the disease. Huntington's disease is an autosomal dominant disorder: when one of the parents carries the mutant gene, 50% of the offspring will inherit the mutation and one day develop the disease. The IT15 gene which causes Huntington's disease is on chromosome 4 and encodes the protein huntingtin. Normal huntingtin contains repeats of an amino acid, glutamine, but mutant huntingtin contains more than 35 to 40 glutamines and induces the disease. Symptom onset occurs earlier when there are more repeats. The work of Frédéric Saudou's team (Inserm) is funded by the Institut Curie, the Ministry of Research, and the CNRS, and is supported by the Fondation pour la Recherche Médicale (FRM), the Fondation BNP-Paribas, the Association pour la Recherche sur le Cancer (ARC), the Association Française contre les Myopathies, the Young Investigator Programme of the European Molecular Biology Organization (EMBO) and Provital. (1) Inserm director of research Frédéric Saudou and Inserm senior research associate Sandrine Humbert work in the "Intracellular signaling and cell death" group of CNRS/Institut Curie Research Unit 146. http://www.jneurosci.org ---------------------------------------------------------------------- To sign-off Parkinsn send a message to: mailto:[log in to unmask] In the body of the message put: signoff parkinsn