le control, paralysis and untimely death.
Healthy "neighbor" or supporting non-neuronal cells also have a protective effect on damaged mutant motor neurons, slowing the progression of ALS even when the nerve cells carry the mutant gene. The researchers speculate that the non-neuronal cells play a vital role in nourishing the motor neurons and in scavenging toxins from the cellular environment.
The onset and progression of disease in inherited ALS is determined by the motor neurons and microglia, small immune cells in the spinal cord, which migrate through nerve tissue and remove damaged cells and debris. Damage to motor neurons determines timing of disease onset. Microglia – the neighborhood, or "helper" cells – are then activated to help nourish the motor neurons and clean out debris like a vacuum cleaner. But because these neighboring cells are also damaged, they hurt instead of help, thus speeding disease progression.
When the UCSD researchers isolated and shut off mutant SOD1genes in the motor neuron cells only, the disease onset slowed, but the course of the disease eventually caught up to the control rodents. When mutant genes in only the microglia were silenced, the scientists found almost no effect on disease onset, however the disease progression was significantly slowed.
This discovery – authored by UCSD investigators Severine Boillee, Koji Yamanaka, Cleveland and others and published in the June 2 issue of the journal Science – confirms the importance of the new therapeutic approach, which delivers an antisense drug directly to the whole nervous system, including non-neuronal cells.
"Limiting mutant damage to microglia robustly slowed the disease's course, even when all motor neurons were expressing high levels of a SOD1 mutant," said Cleveland. "Our research suggests that what starts ALS and what keeps it going are two separate phases; it also suggests that with the right therapy, ALS could become a
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