Observing axonal transport with molecular resolution on molecular timescales

Neurons are cells that electrically transmit information about our surroundings to the brain, process that information in the brain, and transmit instructions for action to the rest of the body. Just like electrical cables, they are long and thin. To function properly, a neuron must move nutrients, waste, and organelles along its length. The neuron does this using tiny motors made from single molecules, which drag their cargo behind them while “walking” along protein fibers inside of the neuron. If these motors break down, or are otherwise prevented from moving their cargo, the neuron can no longer function properly. This type of disfunction has been linked to neurodegenerative disease like Alzheimer’s, ALS, and Parkinson’s.

It is not known how such tiny molecular motors can exert enough force to pull their cargos through the dense, viscous interior of the neuron. The largest, most complicated, and least understood type of motor is called dynein. The individual “steps” of its walking motion are too small and fast to capture using a conventional microscope.  To see the details of this stepping motion we have built a custom microscope capable of unprecedented resolution. It will use fast and sensitive detectors to measure the motion of very bright gold nanoparticles, which we will attach to dynein as its cargo. From this motion we will determine whether dynein truly “pulls” its cargo, or instead acts like a ratchet, relying on small random motions to push the cargo through each step. With a better understanding of how these motors work, we hope to shed light on the underlying causes of some types of neurodegenerative disease.