Huntington's disease deciphered

"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 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."

The study was supported by grants from the Huntington's Disease Society of America, the National Institutes of Health, the Muscular Dystrophy Association, the ALS Association and a Marine Biological Laboratory Summer Fellowship.

Other authors on the study are Yi-Mei You, Sarah Pollema, Agnieszka Kaminska, and Gustavo Pigino of UIC; Katherine Liu of the Marine Biological Laboratory at Woods Hole, Mass.; Katsuji Yoshioka of Kanazawa University, Japan; Benny Björkblom and Eleanor T. Coffey of the Ǻbo Akademi and Turku University in Finland; Carolina Bagnato and David Han of the University of Connecticut Health Center; and Chun-Fang Huang and Gary Banker of the Oregon Health & Science University.