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New mechanism of neuronal toxicity in Huntington's chorea discovered


Mié, 29/02/2012 - 14:22

New mechanism of neuronal toxicity in Huntington's chorea discovered

In the week that marks the celebration of World Rare Disease Day, scientists from the Centre for Genomic Regulation (CRG), have described the mechanism that causes neuronal death in Huntington's chorea. The discovery will advance the development of therapeutic treatments for this rare disease. 
Huntington's Chorea is a rare disease caused by a mutation in the Huntingtin gene (HTT). While the normal gene has a limited number of repetitions of the CAG nucleotide triplet in the DNA chain (around 20), in the mutated gene the CAG number is higher and when it exceeds 40 repetitions the individuals develop a serious neurodegenerative disorder involving a severe lack of motor coordination, cognitive deterioration and psychiatric problems. 
In the latest issue of the journal PLoS Genetics, Mónica Báñez-Coronel, Eulàlia Martí and Xavier Estivill, researchers from the Genetic Causes of Disease research group at the CRG, have provided evidence of the involvement of the HTT’s RNA (ribonucleic acid) and the RNA interference (RNAi) pathway in the pathogenesis of the disease. 
Although the gene for Huntington's disease was identified in 1993 and it was found that the causative mutation is the anomalous expansion of the CAG triplet in the HTT gene, the mechanism by which it caused neuronal death had not been elucidated completely. For many years studies focused on the pathogenic role of the abnormal protein coded for by the mutant HTT gene. The CRG researchers have demonstrated that expression of the mutated gene involves the production of small-sized RNA formed by repetitions of CAG with neurotoxic activity. These sequences, formed due to the repetitions, are increased in the affected areas of the brains of patients with Huntington's as well as in mice models of the disease. These fragments are incorporated into the intracellular gene silencing machinery, that is, they contribute to some genes not being expressed and altering said expression of the genes with lethal consequences in neuronal physiology. 
The activity of the abnormally expressed CAG fragment repeats can be counteracted through the use of complementary sequences, which eliminate the toxic effect. The work paves the way for new therapies aimed at blocking the toxic effects of these CAG fragments in the neurones of patients with the disease. Now that the cause of neuronal damage in this disease is known, specific therapeutic solutions can be sought. 
About the CRG
The Centre for Genomic Regulation is a global benchmark biomedical research institute, created in 2000 by the Catalan government, with the participation of the Pompeu Fabra University and the Ministry of Science and Innovation. Its efforts focus on understanding the complexity of life, from the genome to the cell, up to the entire organism and its interaction with the environment. All this is achieved through a multidisciplinary team connecting biology to physics, mathematics, chemistry and medicine, and with the support of cutting-edge scientific services, helping to create the 'medicine of the future', i.e., personalised medicine tailor-made to the needs of each patient. 
The CRG’s main objectives are the achievement of scientific excellence, communication and the establishment of a bilateral dialogue with society, providing advanced training to the next generation of scientists, and transforming new knowledge into benefit and value to society and the economy of the country. 
Reference article: Bañez-Coronel M, Porta S, Kagerbauer B, Mateu-Huertas E, Pantano L, Ferrer I, Guzman M, Estivill X, Marti E. (2012) A Pathogenic Mechanism in Huntington’s Disease Involves Small CAG-Repeated RNAs with Neurotoxic Activity. PLoS Genet 8(2): e1002481.doi:10.1371/journal.pgen.1002481 
For further information: Laia Cendrós, Press Office, Centre for Genomic Regulation (CRG). Tel. +34 93 316 02 37 - e-mail.