Gene Transfer Boosts Acetylcholine Production and Stimulates Neuromuscular Activity

A publication described a study that analyzed enzymatic activity taking place in the synapses between nerves that directly relates to chronic neuromuscular diseases such as myasthenia gravis.

The presynaptic hemicholinium-3-sensitive, high-affinity choline transporter (CHT) supplies choline for acetylcholine (ACh) synthesis. Hemicholinium-3 (HC3), also known as hemicholine, is a drug, which blocks the reuptake of choline by the high affinity transporter CHT (encoded in humans by the gene SLC5A7) at the presynapse. The reuptake of choline is the rate-limiting step in the synthesis of acetylcholine; hence, hemicholinium-3 decreases the synthesis of acetylcholine.

Investigators at Vanderbilt University (Nashville, TN, USA) worked with mouse models that included a line of genetically engineered mice that lacked the CHT gene.

They reported in the December 29, 2010, issue of the journal Neuroscience that the mice lacked most neuromuscular activity and survived for less than an hour after birth. However, if animals of this genotype were transfected with the gene for the motor neuron promoter Hb9, the mice were able to move and breathe for a postnatal period of about 24 hours. When the Hb9 gene was given to mice with normal CHT, the animals demonstrated an increased capacity for treadmill running compared to wild-type littermates.

"The brain uses acetylcholine for a wide variety of functions, including the ability to sustain attention," said senior author Dr. Randy Blakely, professor of molecular neuroscience at Vanderbilt University. "We reasoned that giving more of this protein might enhance muscle function and reduce nerve-dependent fatigue. The findings could lead to new treatments for neuromuscular disorders such as myasthenia gravis, which occurs when cholinergic nerve signals fail to reach the muscles.”

"Drugs that increase choline transporter activity could represent a novel therapeutic strategy for myasthenia gravis and a wide range of other disorders that involve cholinergic signaling deficits,” said Dr. Blakely.

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