(Philadelphia, PA) - 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).
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. They report their findings in a recent issue
of Nature Cell Biology. 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, as reported in The Journal of Cell Biology,
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. In several further papers
published in the Proceedings of the National Academy of Sciences
and The EMBO Journal, 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
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