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