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Axonal transport impaired in HD
HD Lighthouse Contributing Editor's Comment:


http://www.hdlighthouse.org/showUpdate. ... Number=650
Researchers at the University of Illinois at Chicago College of Medicine have identified
the mechanism by which axonal transport is impaired in neurons in Huntington’s disease.
Using mouse, squid, and cell models of HD, Dr. Scott Brady and Dr. Gerardo Morfini
and colleagues found that the HD protein activates an enzyme called JNK (for cJun Nterminal
kinease) which causes the impairment.
Axons are nerve fibers which project from the neuron and carry electric impulses. The
longest axons in the human body are those of the sciatic nerve which run from the base of
the spine to the big toes of each foot. Axons in the brain are much smaller of course but
are still many times longer than the body of the neuron.
Axonal transport is critical for the survival of neurons. Proteins are synthesized in the
cell body and then are transported in microtubulins or ‘tracks’ which run along axons to
the synapses, the junctions through which neurons signal to each other. Vesicles
containing neurotransmitters are also carried to the synapses for release. When the
transport system becomes impaired, synapases and axons become dysfunctional,
signaling is reduced, and the cell begins to die.
The specific form of JNK which does the damage is JNK3 which is found in the brain
and testes. JNK3 phosphorylates kinesin-1, the motor protein of the axonal transport
system which moves the cargo toward the ends of the axons. Phosphorylation reduces
the ability of kinesin-1 to bind to the microtubules, thus impairing transport.
If the mutant protein impairs such a critical function as axonal transport, then why do
neurons remain healthy for years? As we age, this function becomes less
efficient.
"Ifyou take a hit when you're very young, you still are making more andtransporting more proteins in each neuron than you need," Dr. Bradysaid,  "But as you get older and older, the neuron produces andtransports less.  Each hit diminishes the system further.  Eventually,the neuron falls below the threhold needed to maintain cell health.'
Presymptomatic HD mice were found to have impairment of axonal transport, suggesting
that this is an early pathology in the disease. The researchers have concluded that
inhibiting JNK activation is a promising therapeutic target.
Dr. Brady and his colleagues have also found impairment of axonal transport in
Alzheimers and other neurodegenerative diseases. "There is a common theme and a
common Achilles heel of the neuron that underlies all these diseases," Dr. Brady said.
"We've invented a word, dysferopathy, (from the Greek 'fero', to carry or transport) for
these adult-onset neurodegenerative diseases. All have disruption of the axonal transport
system in common."
Reference:
University of Illinois at Chicago Medical College press release.

-- Marsha L. Miller, Ph.D.

Posted to the HDL:
09-20-2009