Oklahoma Medical Research Foundation Scientist Kenneth Miller, Ph.D.

With the help of a simple little worm, an Oklahoma Medical Research Foundation scientist is unraveling the mysteries of a complex transportation system the brain uses to move the tiny cargoes that contribute to our perceptions, thoughts and memories.
Brain cells, or neurons, have long tentacles called axons, through which they communicate with one another and with muscle cells. Some axons reach lengths as long as 3 feet in humans. To deal with these long distances, neurons have developed an amazing system of tiny “train tracks” and “engines” to quickly carry cargo long distances in both directions. The cargoes consist of tiny membrane sacs called “vesicles” that provide the signals for thoughts and memories, as well as larger sacs called “organelles” that help the neuron grow or repair an injury.
OMRF’s Kenneth Miller, Ph.D., is seeking to understand how the cargo system is regulated to keep us thinking clearly, as well as how defects in the transport system contribute to neurological disorders.
Miller and his colleagues have discovered a new “conductor” that regulates the cargo movements in neurons. The conductor allows the tiny vesicle cargos that are important for our thoughts and memories to stay in axons where they are needed but sends the larger ones (organelles) back to the cell body of the neuron so they won’t clog up the axon or interfere with the signals that help us think and move.
However, Miller said the system can be regulated to allow the larger organelles to move into the axon when they are needed, for example, to help the neuron grow or recover from an injury.
Miller and his team made their discovery using C. elegans, a tiny roundworm with a simple nervous system. The new findings were published in back-to-back papers in the scientific journal Genetics.
“Neurons actively shuttle their cargo along tracks using motor proteins that essentially act as engines,” said Miller. “The motors literally walk along these tracks, shouldering their cargo. We have found a neuron-specific transmission system for regulating the connection between one of these motors and its cargo.”
Neurons have several kinds of motors that can move cargo outward, but only one, known as dynein, can move cargo back into the cell body. Miller and colleagues discovered a new function in neurons, which they named the CSS system. The CSS system seems to act as part of dynein’s transmission system, determining whether or not the motor engages with cargo. Miller noted that a recent study found that as many as 14 neuronal diseases are connected to the dynein motor.
“We still don’t understand the basis of a lot of neurological disorders, because we’re still learning how nerve cells work,” said Miller. “But this discovery gets us one step closer to revealing how the most complex cells in our bodies function at a molecular level. Once we understand how things are supposed to work at that level, we may be able to treat a person with a neurological disorder by targeting the malfunction with a drug or using new methods of gene therapy.”
“It’s remarkable how studies of a tiny worm that has a very simple nervous system can be the key to unlocking a very complicated process that nerves use,” said OMRF Vice President of Research Paul Kincade, Ph.D. “Every cell in the body has complex components, and in the case of neurons, it’s important to sort what goes out and what comes back. Miller has used very elegant experimental approaches to identify one of the key players in this intricate process.”
This research is funded by grant R01GM080765 from the National Institute of General Medical Sciences and the Oklahoma Center for the Advancement of Science and Technology grant HR14-003.