Protein Blockage Causes Motor Neuron Disease

Using a transgenic mouse model, researchers have shown that an accumulation of dynamitin can cause motor neuron degeneration such as that observed in amyotrophic lateral sclerosis (ALS). Their study, published in the May 30, 2002, issue of Neuron, was designed to test the hypothesis that disruption of neuronal transport could account for the development of motor neuron disease.

A line of mice was engineered that overexpressed dynamitin, an element of the complex that binds and transports protein along the axons. The investigators, from the University of Pennsylvania (Philadelphia, USA), found that mice overexpressing dynamitin displayed a late-onset progressive motor neuron degenerative disease characterized by decreased strength and endurance, motor neuron degeneration and loss, and denervation of muscle.

Dynamitin overexpression was found to disassemble dynactin, a required activator of cytoplasmic dynein, resulting in an inhibition of retrograde axonal transport. "Our mouse model shows that disruption of this neuronal transport is sufficient to cause motor neuron degeneration,” explained Dr. Erika Holzbaur, who led the research team. "We hypothesize that, in humans, different insults (either inheritable or environmental) may lead to disruptions in this continuous transport process. Once it is disrupted, the health of the neuron will decline over time, resulting in the motor neuron degeneration seen in ALS.”

The investigators suggest that in light of these findings, future therapies for motor neuron diseases should seek to restore the normal flow of protein in motor neurons.



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