Discovery of Agile Molecular Motors Could Aid in Treating Motor Neuron Diseases

Over the last several months, the labs of Yale Goldman, MD, PhD, Director of the Pennsylvania Muscle Institute at the University of Pennsylvania School of Medicine, and Erika Holzbaur, PhD, Professor of Physiology, have published a group of papers that, taken together, show proteins that function as molecular motors are surprisingly flexible and agile, able to navigate obstacles within the cell. These observations could lead to better ways to treat motor neuron diseases.
Motor neuron diseases are a group of progressive neurological disorders that destroy motor neurons, the cells that control voluntary muscles for such activities as speaking, walking, breathing, and swallowing. When these neurons die, the muscle itself atrophies. A well-known motor neuron disease is amyotrophic lateral sclerosis (ALS, commonly known as Lou Gehrig's disease).


Possible models for the bi-directional movement observed in the dynein-dynactin molecular motor along microtubules. A) Random, diffusive motions; B) Flexible rotation of the dynein ring; and C) Steps dictated by the microtubule lattice. (Credit: Jennifer L. Ross, PhD, University of Pennsylvania School of Medicine; Nature Cell Biology)

Using a specially-constructed microscope that allows researchers to observe the action of one macromolecule at a time, the team found that a protein motor is able to move back and forth along a microtubule – a molecular track – rather than in one direction, as previously thought. The proteins in this motor, dynein and dynactin, are the "long-distance truckers" of the cell: working together, they are responsible for transporting cellular cargo from the periphery of a cell toward its nucleus.
"My lab concentrates on the cellular and genetic aspects of the dynein-dynactin motor, while Yale's group delves into the mechanics of the motor itself," says Holzbaur. "We're deconstructing the system to understand how it all works in a living cell. In the lab, we start with a clean microtubule with a motor walking across it, but in the cell it's different: microtubules are packed together, with proteins studded along them, and cellular organelles and mitochondria are crammed in. The motor needs to maneuver around those 'obstructions.'" Goldman and Holzbaur suggest that the ability of the dynein-dynactin motor to move in both directions along the microtubule may provide the necessary maneuvering ability to allow for effective long distance transport.
Earlier this year, researchers in Holzbaur's lab found that a mutation in dynactin leads to degeneration of motor neurons, the hallmark of motor neuron disease. This mutation decreases the efficiency of the dynein-dynactin motor in "taking out the trash" of the cell, and thus leads to the accumulation of misfolded proteins in the cell, which may in turn lead to the degeneration of the neuron.
Scientists are now finding that many other molecular motors are remarkably flexible in their behavior. Goldman and colleagues at the University of Illinois found that a "local delivery" motor, termed myosin V, moves cargo with a variable path short distances along another type of cellular track called actin. This flexibility could help myosin V navigate crowded regions of the cell where the actin filaments criss-cross and where other cellular components would otherwise pose an impediment to motion. Defects in myosin V function also result in neurological defects.
Most of these molecular motors are associated with specific diseases or developmental defects, so understanding the puzzling aspects of their behavior in detail is necessary for building nanotechnological machines that, for example, could replace defective motors. "The ultimate goal is to find ways to treat motor neuron disease as well as other diseases that involve cellular motors and also construct nano-scale machines based on these biological motors," says Goldman.
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