Hereditary ALS linked to low electric charge in cells

In an article in the scientific journal The Journal of Biological Chemistry, Mikael Oliveberg, professor of biochemistry at Stockholm University in Sweden, describes how disturbances in these functions underlie the hereditary form of the motor-neuron disease Amyotrophic Lateral Sclerosis (ALS).

“Genetic studies have recently shown that even tiny disturbances in this balance of charges are one of the factors that cause the hereditary form of ALS. The disease is basically tied to the SOD1 protein suddenly starting to aggregate in small lumps in the nerve cells of the spinal cord and at the same time withering and dying. When this happens the musculature becomes paralyzed,” says Mikeal Oliveberg.

Normally SOD1 proteins avoid this inappropriate lumping because their surfaces are adorned with some 40 negative charges. But if only one of these charges is lost, the disease is incurred-­the proteins can no longer remain soluble. A mystery in this context is that patients who were born with this faulty SOD1 protein remain fully healthy for their first 50-60 years of life. In some way the cells manage to compensate for the faulty proteins, but this capacity is eventually lost with aging.

“The goal is to be able to stimulate the built-in defense mechanisms that keep us healthy during the first half of our lives so that they have the vigor to keep working a few more years. To do this we need to learn more about why nerve death escalates so suddenly and, above all, so predictably at the molecular level,” says Mikael Oliveberg.

Similar mechanisms underlie several other feared protein disorders like Alzheimer's and Parkinson's. The discovery that charges play such a critical role in ALS is an important step toward understanding these processes in a broader perspective.

“Another puzzle is why red deers seem to get along with an SOD1 protein that has a substantially lower negative charge than that in humans. Perhaps their cellular defense mechanisms are tuned differently, or could it be that old elks in fact have a higher propensity to perish from ALS-like symptoms? It would be interesting to hear whether anybody knows anything about this,” says Mikael Oliveberg.

Amyotrophic Lateral Sclerosis-associated Copper/Zinc Superoxide Dismutase Mutations Preferentially Reduce the Repulsive Charge of the Proteins, The Journal of Biological Chemistry, Vol. 282, Issue 29, 21230-21236, JULY 20, 2007

Erik Sandelin; Anna Nordlund; Peter M. Andersen; Stefan S. L. Marklund; Mikael Oliveberg, Stockholm University.