The prevailing idea about Huntington's disease is that the mutant protein damages a subset of neurons - including pyramidal - by exerting its toxicities within them.

But in research published in the May 5, 2005, issue of Neuron, scientists from the University of California at Los Angeles, as well as Cornell University's Medical School, Rockefeller University in New York, Atlanta's Emory University, the Riken Brain Science Institute, and Japan Science and Technology Agencies, both in Saitama, Japan, use conditional gene expression to suggest that it is the production of that mutant protein in another type of neuron, and the interaction between the two, that might be what's causing damage.

The paper is noteworthy for both its methods and its findings. Senior author William Yang told BioWorld Today that "the study utilized a conditional expression strategy to tease out where expression of a global genetic defect causes neuronal damage in a neurodegenerative disorder."

The genetic defect underlying Huntington's disease is simple: A so-called repeat expansion of the DNA triplet CAG, which encodes the amino acid glutamine, leads to the insertion of too many glutamines into the protein huntingtin. That causes the mutant protein to misfold and sets off a neurodegenerative cascade that leads to motor, cognitive and psychiatric symptoms, and ultimately death.

Mutant huntingtin is produced in multiple brain areas, but damage is concentrated in two cell types: pyramidal neurons of the cortex and medium spiny neurons in the striatum, a brain region that receives input from the cortex.

The scientists developed two groups of mouse models with mutant huntingtin expressed in different patterns. One group expressed the mutant huntingtin protein throughout the brain, while the other had expression of the mutant protein restricted to pyramidal neurons in the cortex.

To their surprise, the scientists found that expressing mutant huntingtin in only cortical pyramidal neurons led to - well, not much of anything. While the current scientific theory is that the accumulation of mutant huntingtin in cortical pyramidal neurons is what damages those neurons, the researchers found that mice with mutant huntingtin in only the cortical pyramidal neurons showed very little degenerative processes, and no motor deficits at any age.

In electrophysiological experiments designed to further probe the cellular consequences of mutant huntingtin expression in different cell types, the researchers found that global but not pyramidal neuron-only knockouts had less active cortical inhibitory interneurons, which would be expected to lead to hyperactive cortical neurons. Yang and his colleagues believe that the interaction between cortical interneurons and cortical pyramidal neurons might play a role in initiating neurodegeneration observed in Huntington's disease.

To Yang, the most surprising aspect of the study was that the phenomenon is so robust. "We originally designed the cortical experiments to see if striatal disease is due to [pyramidal neuron] damage in the cortex. But we found that if the mutant gene is only expressed in cortex, not only do you not get striatal disease, but you don't really get any cortical disease," he said.

The experiments are not a straightforward comparison of the consequences of two different cell types expressing huntingtin; as a side effect of the experimental design, they also compared the effects of more and less damage to the brain. Yang agreed that his results also were consistent with the idea that "the more neurons you are affecting, the more disease there will be."

"What our mouse model demonstrates," he added, "is that damage to one particular neuronal cell type that has always been considered vulnerable requires damage to another neuronal type by mutant huntingtin."

Yang and his colleagues plan to make mice with mutant huntingtin restricted to different cell types, to tease out in which cell types expression of the protein is necessary and/or sufficient to cause disease. "We don't know the minimum cell type requirements for pathogenesis of Huntington's disease, and that's what we are working on now," Yang said. For example, "if you need multiple cell types expressing the mutant protein to develop Huntington's, and turning off mutant huntingtin expression in one such cell type is sufficient to stop the disease, then targeting that cell type for therapy would be a great strategy."

Additionally, the findings suggested that preclinical drug discovery might profit from taking cell-cell interactions into account at the initial screening stage. "Drug screening in Huntington's disease has been focused on intracellular toxicities of the mutant protein," Yang said. "We hope that understanding the mechanisms underlying pathological cell-cell interactions may provide additional therapeutic targets for Huntington's disease."