Perhaps one of the most astonishing features of the human nervous system is the fact that muscles in one part of the body, for example the feet, can be controlled by neurons whose cell bodies are located extremely far away in the spinal cord.
These cell bodies therefore must extend processes incredibly long distances. As most of the proteins in a neuron are made in the cell body, the transport of proteins and other molecules through these very long processes called axons is critically important for proper motor control.
In certain neurodegenerative diseases in which motor control is impaired, e.g., amyotrophic lateral sclerosis, traffic along the axons slows down and certain molecules accumulate. Could this cellular “traffic jam” be responsible for the degenerative phenotype and associated muscular atrophy?
A research team led by Erika Holzbaur has addressed this question by generating transgenic mice with a specific defect in axonal transport. Their findings are reported in the May 30 issue of Neuron.
Holzbaur and colleagues engineered mice that produced an excess of protein called dynamitin in their mature neurons. Dynamitin is normally part of a complex that binds and transports protein along the axons. However, when there's too much dynamitin, this complex stops functioning.
The transgenic mice developed the symptoms of motor neuron disease after a few months of producing excess dynamitin. In their neurons, transportation of proteins through the axon had slowed down and certain molecules had accumulated.
“Our mouse model shows that disruption of this neuronal transport is sufficient to cause motor neuron degeneration,” says Holzbaur. “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”.
Bernadette LaMonte, the first author of the study, notes that the mice display a late-onset progressive degeneration that resembles the decline seen in ALS patients.
In the light of these findings, future therapies for motor neuron diseases should seek to restore the normal flow of protein in motor neurons, the authors suggest.
[Contact: Erika Holzbaur]