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Huntington's disease deciphered
Date:6/14/2009

synthesized to the synaptic terminals where they are needed.

A neuron's critical role in making connections may require it to make the cellular trunk, called an axon, between the cell body and the synaptic terminal to be very long. Some cells have axons that reach half the body's length -- for a tall person, a meter or more. But even in the brain, axonal projections are very long compared to other cells. In addition to the challenge of distance, neurons are very complex cells with many specialized areas necessary to carry out synaptic connections, requiring a robust transport system.

"Inhibition of neuronal transport is enough to explain what is happening in Huntington's," said Brady. Loss of delivery of materials to the terminals results in loss of transmission of signals from the neuron. Loss of signal transmission causes the neurons to begin to die back, leading to reduced transmissions, more dying back and eventual neuronal cell death.

This mechanism also explains the late onset of the disease, Brady said. Activation of JNK3 reduces transport but does not eliminate it. Young neurons have a robust transport system, but transport gradually declines with age.

"If you take a hit when you're very young, you still are making more and transporting more proteins in each neuron than you need," Brady said. "But as you get older and older, the neuron produces and transports less. Each hit diminishes the system further. Eventually, the neuron falls below the threshold needed to maintain cell health."

Brady's group has also linked this pattern of progressive neurodegeneration -- marked by a loss of signaling between neurons, a slow dying back of neurons, and eventual neuron death -- to damage to the transport system in several other hereditary adult-onset neurodegenerative diseases and to Alzheimer's disease.

"There is a common theme and a common Achilles heel of the neuron that underlies all these diseases," Brady sai
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Contact: Jeanne Galatzer-Levy
jgala@uic.edu
312-996-1583
University of Illinois at Chicago
Source:Eurekalert

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