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Differential regulation of dynein and kinesin motor
proteins by the microtubule associated protein tau. The Penn group
found that dynein, which carries loads towards the interior of the
nerve cell, maneuvers around tau; whereas, kinesin, which carries
loads towards the outside of the nerve cell, detaches when it
encounters tau.
Credit: Ram Dixit, PhD, University of Pennsylvania
School of Medicine.
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�Our findings show a mechanism of regulating
the transport of nutrients, signaling molecules, and waste proteins
along a nerve cell�s axon,� says Dixit. �Neurodegenerative diseases
such as Alzheimer�s arise when pieces of this shipping system goes
awry.�
The transport performed by dynein and kinesin is required for
continuously providing new proteins to the axon and synapse to
maintain normal cellular function, and is also required to remove old,
misfolded, or aggregated proteins for degradation. Just as important,
this transport is required for moving other proteins from the
nerve-cell synapse back to the cell body, which is also required to
maintain healthy neurons.
In neurons, microtubules are abundantly decorated with tau. Dynein and
kinesin encounter the tau molecules on their travels along the
microtubules. The Penn group found that dynein, which carries loads
towards the interior of the cell, maneuvers around tau; whereas,
kinesin, which carries loads towards the outside of the cell, detaches
when it encounters tau.
These findings appeared online January 17,
2008, in Science in advance of print publication.
Dynein and kinesin�s individual maneuverings when encountering tau
allow for the cell to be able to offload cargo where it needs to go
with fine-tune accuracy. �Tau may determine where kinesin offloads
cargo along the microtubule tracks that radiate out to the cell
surface from the center,� says Holzbaur. �And dynein�s ability to back
up and go around when it encounters an obstacle such as tau may be a
mechanism to ensure that it gets to the center of the cell with its
important cargo.�
The group conducted studies using single molecules moving along a
tau-decorated microtubule to determine the effects of tau on dynein
and kinesin�s movement. Mutations in molecular motors such as dynein
and kinesin can lead to degeneration of neurons. These mutations, for
example, decrease the efficiency of dynein and kinesin. This problem
can lead to the accumulation of misfolded proteins in the cell, which,
in turn may lead to the degeneration of the neuron.
�There�s a growing theme that defects in transport are tightly
associated with neurodegeneration,� says Holzbaur. �It�s already been
shown in Alzheimer�s disease that there is a change in the
distribution of tau along microtubules. Instead of kinesin getting its
cargo closer to the cell�s outer surface, tau accumulates in the cell
body and kinesin�s cargo of newly synthesized proteins gets dropped
early, not at the cell surface, thus causing problems. Our findings
explain how that can happen.�
This work was supported by the National Institute of Arthritis and
Musculoskeletal and Skin Disease and the National Science Foundation.
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