Although a mutated protein is known to be the ultimate cause of Huntington's disease, how the mutation kills neurons is a mystery. Two research teams now point the finger at disruption of a mechanism for transporting vital molecules down the length of neurons.
People suffering from Huntington's disease--a dwindling of neurons that slowly cripples and eventually kills--carry a mutant form of a protein called huntingtin. One reason that might lead to problems is the location of normal huntingtin protein: It clusters around the internal network that transports vesicles filled with essential molecules down axons, the long extensions that connect neurons.
To check for mischief along this intracellular highway, a team led by Lawrence Goldstein, a cell biologist at the University of California, San Diego, designed small RNA molecules to block the expression of the huntingtin protein in fruit flies. They also created fruit flies that express the mutant version of huntingtin found in human patients. Like a rush-hour traffic jam, both the expression of mutant human huntingtin and inhibition of normal fruit fly huntingtin halted the movement of vesicles within the flies' neurons, killing the flies at the larval stage, the team reports in the 25 September issue of Neuron.
In the same issue, another study of mutant huntingtin reaches the same conclusion. A team led by Scott Brady, a cell biologist at the University of Illinois, Chicago, introduced a shortened form of mutant huntingtin protein into the giant squid axon, which is well characterized. As in the fly neurons, the mutant protein disrupted axonal transport in both directions.
Brady suggests that drugs could be designed to restore axonal transport and perhaps slow or block neurodegeneration. But first, cautions Albert La Spada, a neurogeneticist at the University of Washington, Seattle, it will be important to determine that the defect in axonal transport occurs in Huntington's patients, and if so, that it is actually a cause--not an effect--of whatever kills neurons in Huntington's patients.