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).
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.
Source: University of Pennsylvania School of Medicine
Published on 25th
JULY 2006
