Researchers have identified the mechanism by which axonal transport is impaired in neurons in HD.
Researchers at the University of Illinois at Chicago College of Medicine have identifiedthe 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.
"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," Dr. 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 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."
University of Illinois at Chicago Medical College press release.
Dr. Scott T. Brady
Selected vulnerability of neurons in Huntington's disease suggests that alterations occur in a cellular process that is particularly critical for neuronal function. Supporting this idea, pathogenic Htt (polyQ-Htt) inhibits fast axonal transport (FAT) in various cellular and animal models of Huntington's disease (mouse and squid), but the molecular basis of this effect remains unknown. We found that polyQ-Htt inhibited FAT through a mechanism involving activation of axonal cJun N-terminal kinase (JNK). Accordingly, we observed increased activation of JNK in vivo in cellular and mouse models of Huntington's disease. Additional experiments indicated that the effects of polyQ-Htt on FAT were mediated by neuron-specific JNK3 and not by ubiquitously expressed JNK1, providing a molecular basis for neuron-specific pathology in Huntington's disease. Mass spectrometry identified a residue in the kinesin-1 motor domain that was phosphorylated by JNK3 and this modification reduced kinesin-1 binding to microtubules. These data identify JNK3 as a critical mediator of polyQ-Htt toxicity and provide a molecular basis for polyQ-Htt-induced inhibition of FAT.