London, June 15 (ANI): A new study conducted by scientists at the University of Illinois at Chicago College of Medicine has shed new light on how the mutated huntingtin gene acts on the nervous system to create the devastation of Huntington's disease, an adult onset neurodegenerative disease marked by progressive mental and physical deterioration.
The researchers write in their study report that the mutated huntingtin gene activates a particular enzyme, JNK3, which is expressed only in neurons.
They have also revealed what effect the activation of this enzyme has on neuron function.
Scott Brady, professor and head of anatomy and cell biology at the UIC College of Medicine, underscores the fact that it has been known for long that people who develop Huntington's disease have mutations in the huntingtin gene.
"There are several puzzling aspects of this disease. First, the mutation is there from day one. How is it that people are born with a perfectly functioning nervous system, despite the mutation, but as they grow up into their 30s and 40s they start to develop these debilitating symptoms? We need to understand why the protein is bad at 40 but it wasn't bad at 4," Nature magazine quoted Brady, one of the lead researchers behind the study, as saying.
He said that another problem lies in the fact that the only part affected by the disease is the nervous system, despite the fact that the gene is expressed in other parts of the body also.
Brady and his colleagues began looking for a mechanism that could solve the puzzle, and found that at extremely low concentrations, huntingtin was a potent inhibitor of axonal transport, the system within the neuron that 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," said Brady.
Loss of delivery of materials to the terminals results in loss of transmission of signals from the neuron. That, in turn, causes the neurons to begin to die back, leading to reduced transmissions, more dying back and eventual neuronal cell death.
Brady says that this mechanism also explains the late onset of the disease.
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. 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 said.
The researchers also link 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. 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," Brady said.
The findings have been reported in the online edition of the journal Nature Neuroscience. (ANI)