New study identifies protein crucial in formation of new motor neurons

Catherina Becker is a Packard-funded investigator.

Loss of motor neuron function is the hallmark of ALS.  Since these cells don't naturally regenerate in adult humans, scientists have spent years searching for factors that might enable ALS patients to regrow motor neurons. Packard scientist Catherina Becker, from the University of Edinburgh's Centre for Neuroregeneration, and her colleagues believe they have found such a factor. Using a small aquarium favorite known as a zebrafish (Danio rerio), Becker and colleagues found that blocking the action of a protein called Notch-1 allowed adult zebrafish to regrow motor neurons.

Catherina Becker, a researcher from the University of Edinburgh

Previous studies in rats had led researchers to believe that the expression of a family of proteins called Notch, known to be involved in the embryonic development of the brain, liver, vascular, and other systems, prevented the growth of new motor neurons in adult mammals. As in mammals, adult zebrafish don't typically generate new motor neurons; unlike mammals, they can stimulate motor neuron growth after an injury. Becker and colleagues hypothesized that the expression of the Notch-1 protein would be decreased in new post-injury spinal cord of zebrafish.

Becker and colleagues created a small lesion in the spinal cords of healthy adult zebrafish and looked at which proteins were activated as the fish regrew neurons in response to the injury. Surprisingly, expression of the notch-pathway associated genes was upregulated in spinal progenitor cells and new motor neurons. When Becker and colleagues told the spinal progenitor cells to produce more Notch-1, however, the scientists found that neuron regeneration stopped. Alternately, when Becker blocked the action of Notch-1 using a compound called DAPT, motor neuron regeneration increased.

The researchers concluded that "spinal motor neuron regeneration can be augmented in an adult vertebrate by inhibiting Notch signaling." The development of a pharmaceutical compound that can block the action of Notch-1 may someday have therapeutic potential for ALS.