GluN3A subunits of NMDA-type glutamate receptors, new therapeutic targets against Huntington’s disease

A scientific study describes that GluN3A subunits of NMDA receptors that interact with glutamate —the main exciting neurotransmitter in the nervous system— are therapeutic targets against Huntington’s disease. The new study, published on the latest issue of Nature Medicine, is signed by an international group in which the experts Jordi Alberch, Albert Giralt and Jesús Torres-Peraza, from the Department of Cell Biology, Immunology and Neurosciences of the Faculty of Medicine of the UB and the Group on Cellular Biology of Pathological Processes (Neuroscience Area) of August Pi i Sunyer Biomedical Research Institute (IDIBAPS) have collaborated. The research has been carried out together with the group led by Dr Isabel Pérez Otaño, from the Center for Applied Medical Research (CIMA) and the University of Navarra, among other institutions.

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Huntington’s disease is a progressive and irreversible neurodegenerative disorder that is caused by a mutation of the gene which codifies the protein huntingtin (HTT). Described in 1872 by George Huntington in a North American family lineage, it is an inherited disease caused by an expanded polyglutamine repeat in huntingtin. In Western countries, it occurs in five/seven subjects out of 100,000. It is a rare disease which mainly affects basal ganglia and causes severe motor, cognitive and psychiatric disturbances.


A pharmacological untreated rare disease

According to Professor Jordi Alberch, who heads the Consolidated Research Group of Pathophysiology of Neurodegenerative Diseases of the UB and the research group on Huntington’s disease of the Centre for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), “if one of the progenitors has Huntington’s disease, children have a 50 per cent chance of getting it. Nowadays, we know the genetic base of the disease but there is not any effective treatment”. “In other words —adds the expert—, we know the gene mutation responsible for the disease, but we do not know the molecular mechanism that causes the progressive breakdown of nerve cells in the brain”.

Remarkable advances have been done in basic research on Huntington’s disease; however, an effective treatment has not been found yet. Dr Alberch affirms that “the new work, based on a preclinical multidisciplinary experimental approach, will contribute to design new treatment strategies against the disease”. Professor Jordi Alberch also leads an internationally prestigious research group on motor and cognitive disturbances that characterize Huntington’s diseases and other basal ganglia neurodegenerative diseases.


Glutamate, a powerful neurotransmitter

NMDA-type glutamate receptors (N-methyl-D-aspartate) are macromolecular structures composed by different subunits (GluN1A, GluN2A, GluN3A) which can show some variants. The UB expert Albert Giralt, first author of the paper together with Sònia Marco, highlights that “NMDA receptors play a major role in brain’s functions; they regulate the memory and learning processes and they are involved in diseases such as schizophrenia or Alzheimer’s”.

“Up to now —explains Dr Giralt, who received the Young Research Award conferred by CIBERNED in 2012—, clinical studies which analysed NMDA’s function did not have any kind of specificity; that is why they have not been successful. Our results show a new possibility to produce more specific drugs against some particular NMDA subunits —GluN3A or NR3A— in order to improve significantly Huntington patients’ symptomatology”.

The new research, funded by the National R+D Plan and CHDI Foundation, will foster the research on rare diseases, a group of disease that affect to a small percentage of the population. Besides, pharmaceutical companies are not interested in them. The research aims at promoting future research lines on NMDA receptors action in severe neurodegenerative diseases in order to design neuroprotective therapies targeting GluN3A or pathogenic Htt-PACSIN1 interactions which might prevent or delay Huntington’s disease progression.


Source: Universitat de Barcelona

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