Mutated huntingtin gene inhibits neuronal transport by activating an enzyme found only in neurons, according to study in Nature Neuroscience.


A team of researchers has discovered how the mutated huntingtin gene acts on the nervous system. They found that the gene activates an enzyme called JNK3, which is expressed only in neurons. This in turn suppresses neuronal transport, which over time leads to neuronal cell death.

Their findings appear in Nature Neuroscience online in a paper titled “Pathogenic huntingtin inhibits fast axonal transport by activating JNK3 and phosphorylating kinesin.”

The scientists set out to understand two aspects of Huntington’s disease: why symptoms only develop later in life even though a person is born with the mutated gene and why the mutation only affects the nervous system even though it is present elsewhere.

They found that at extremely low concentrations, huntingtin was a potent inhibitor of axonal transport through the activation of JNK3. The axonal transport system within the neuron shuttles proteins from the cell body where they are synthesized to the synaptic terminals where they are needed.

“Inhibition of neuronal transport is enough to explain what is happening in Huntington’s,” according to Scott Brady, Ph.D., professor and head of anatomy and cell biology at the University of Illinois at Chicago College of Medicine. “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, Dr. Brady adds. Activation of JNK3 reduces transport but does not eliminate it. Young neurons have a robust transport system, but transport gradually declines with age.


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