Running Out of Gas At The Neuromuscular Junction

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Neurological Problems

The process by which neurons communicate with other cells literally runs out of "gas", or energy, when little bodies called mitochondria are missing, said Baylor College of Medicine researchers in a report in the current issue of the journal Neuron.

The finding could have implications for human metabolic diseases associated with mitochondria, said Dr. Hugo Bellen, professor of molecular and human genetics at BCM, director of the program in developmental biology, and a Howard Hughes Medical Institute investigator.

The defect occurs in part because of the unique morphology and physiology of the neuron, said Bellen. The body of the neuron is located in the central nervous system and sends out a long projection, called an axon, to the periphery. The small bodies called mitochondria provide energy to the cell and are normally present all the way at the terminals of these long projections, the synapse, where neurons communicate with their target cell.

A protein called dynamin-related protein is crucial to the ability of mitochondria to divide. In studies in fruit flies, Bellen and his colleagues found that when the mitochondria cannot divide, they remain clustered around the nerve cell nucleus and fail to travel to the synapses. This means that they cannot produce energy at the site where a lot of energy may be required.

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The problem is in the fundamental mechanism by which cells release neurotransmitters, the key elements of intercellular communication. In the synapse, neurotransmitters are transported in little vesicles. Vesicles are formed from the membrane at specific sites, loaded with neurotransmitters, transported to the proper release site, and released into the membrane when the neuron is stimulated.

Because some energy can be produced in the synapse in the absence of mitochondria, the overall process works almost normally when not challenged. However, when the nerve cell is used over and over again, as during exercise, energy runs out. Bellen and colleagues showed that when energy levels are low, the transport of vesicles is greatly impaired.

"The synapses wear out because the transport of vesicles is mediated by a protein called myosin, which requires a lot of energy," said Bellen, thereby providing an elegant explanation why vesicles are not transported properly, resulting in defects in intracellular communication.

In other words, when there are no mitochondria in nerve terminals, the process affected is that which requires the most energy. In this case, it involves the transport of vesicles, which carry crucial neurotransmitters, to the site of release. This may explain why some patients who have problems with mitochondrial transport exhibit neurological problems.

Major contributors to the research were Dr. Patrik Verstreken and Cindy V. Ly. Also involved in the study were Koen J.T. Venken, Tong-Wey Koh, and Yi Zhou. HOUSTON - (August 4, 2005)

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