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Normal Brain Electrical Activity Protects Nerves from Huntington's Disease Peptides

By BiotechDaily International staff writers
Posted on 02 Dec 2009
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The normal level of brain electrical activity (normal synaptic activity) protects nerve cells from the affect of the toxic peptides that characterize Huntington's disease.

Huntington's disease is a neurodegenerative disorder caused by a mutation in the gene that encodes for the huntingtin (Htt) protein. The mutated gene adds from one to many dozens of extra glutamine molecules to Htt. Incomplete breakdown of the enlarged protein results in the buildup of toxic, misfolded peptides that destroy cells in the nervous system.

Working with a mouse model of Huntington's disease, investigators at the Burnham Institute for Medical Research (La Jolla, CA, USA) examined the part played by brain electrical activity on the interaction between nerve cells and toxic Htt peptides.

They reported in the November 15, 2009, online edition of the journal Nature Medicine that normal synaptic receptor activity made nerve cells more resistant to Htt peptides. In contrast, excessive extrasynaptic electrical activity contributed to increased nerve cell death.

Treatment of mice that had been transfected with Htt peptides with low doses of the drug memantine, which is used to treat Alzheimer's disease, was found to effectively protect the animals' nerve cells. This was due to the action of the drug in reducing excessive NMDA-type glutamate receptor activity (synaptic N-methyl-D-aspartate-type glutamate receptor activity), which prevented the expression of excessive extasynaptic activity. However, high-doses of memantine stimulated disease progression, as it also blocked lower level protective synaptic NMDA receptor activity.

"Chronic neurodegenerative diseases like Huntington's, Alzheimer's and Parkinson's are all related to protein misfolding," said senior author Dr. Stuart A. Lipton, professor of neurosciences at the Burnham Institute. "We show here, for the first time, that electrical activity controls protein folding, and if you have a drug that can adjust the electrical activity to the correct levels, you can protect against misfolding. Also, this verifies that appropriate electrical activity is protective, supporting the ‘use it or lose it theory' of brain activity at the molecular level. For example, this finding may explain why epidemiologists have found that "using" your brain by performing crossword puzzles and other games can stave off cognitive decline in diseases like Alzheimer's."

Related Links:
Burnham Institute for Medical Research



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