Friday April 18 2008
CEA
Huntington’s Disease: role of dopamine in the regulation of neuron metabolism
Hum Mol Genet. In press
CEA
to develop new therapeutic treatments for neurological diseases
MIRCen teams have just reported that dopamine, which is one of the main neurotransmitters1 in the brain, escalates neuronal death in the striatum, which is the brain region most vulnerable to lesional damage in many neurological diseases, including Huntington’s disease.
Huntington’s disease leads to the degeneration of neuronal cells, affecting cognitive and motor functions and causing dementia. These psychiatric manifestations are compounded by neurological manifestations, where fully conscious subjects show uncontrollable, uncoordinated and abnormal body movements (chorea), and lack of balance.
Huntington’s disease is characterised in particular by degeneration in a specific brain region called the striatum. There is still no known therapy that will efficiently slow the progression of this disease. However, we continue to improve our understanding of the mechanisms underlying the disease.
Research has already highlighted the role of mutant huntingtin, which is the protein that causes the disease and has particularly high toxicity against striatal cells.
In 2004, MIRCen researchers searching to better understand how mutant huntingtin triggers striatal neuron death joined forces with the SHFJ and an iBiTecS2 team to test the hypothesis that dopamine, which is one of the brain’s main neurotransmitters and is largely concentrated in the striatum, could promote neuronal death. The results of this research drive, which are now available, confirm that mutant huntingtin-induced striatal neuron death escalates in the presence of dopamine. This escalation is due to the fact that dopamine acts on specific receptors found in cell membranes to significantly alter the mitochondria, which are the main suppliers of energy to the cell. These results were obtained through novel methods, including the use of viral vectors (genetically-modified viruses that lead to highly efficient upregulation of a broad range of human neuronal proteins).
The CEA teams have thus demonstrated a new cellular pathway that a neuron can use to subtly regulate the energy consumption of another neuron by ‘talking’ to it remotely, which it does via an intermediary – a neurotransmitter. This research opens up possibilities for devising novel therapeutic strategies for Huntington's disease in the longer term. This research is now pressing on with animal studies, in collaboration with Pierre & Marie Curie University in Paris and Columbia University in New York.
1 A neurotransmitter is a ‘messenger’ molecule that governs the transmission of information between nerve cells.
2 Institute of Biology Technologies - Saclay
Ref: Benchoua A, Trioulier Y, Diguet E, Malgorn C, Gaillard MC, Dufour N, Elalouf JM, Krajewski S, Hantraye P, Déglon N, Brouillet E (2008). Dopamine determines the vulnerability of striatal neurons to the N-terminal fragment of mutant huntingtin through the regulation of mitochondrial complex II. Hum Mol Genet. In press