Research Reveals How ALS Spreads Through Body

A new discovery about how amyotrophic lateral sclerosis (ALS) spreads throughout the body has led Canadian researchers to believe new therapeutic approaches could be developed to stop it.

Currently, there is no cure for ALS and its causes are unknown. But this new research has shed some light on how the disease is transmitted throughout the nervous system. The findings appear in the most recent issue of the Proceedings of the National Academy of Sciences.

The most common form of motor neuron disease, ALS is associated with mutation and misfolding of the Cu/Zn superoxide dismutase (SOD1) protein. Previous studies have established that mutant misfolded versions of this protein can cause non-mutant forms to misfold inside living cells. This new study suggests that the misfolded version can then be transmitted between cells, perpetuating the mutation process and spread of the disease.

“Wild-type, non-mutated SOD1 can participate in a ‘prion-like’ spread of misfolding within the nervous system, and this process can be blocked by antibodies that target misfolded SOD1, while sparing normal SOD1,” says lead researcher Neil Cashman, MD, a professor at the University of British Columbia in Vancouver, where he is also Canada Research Chair in Neurodegeneration and Protein Misfolding. “These discoveries in cell culture point to a rational therapeutic approach to all types of ALS.”

Cashman and his colleagues were able to identify two mechanisms by which this transmission between cells may occur—either by clumps of proteins that are released from dying cells or by smaller transporter vesicles inside the living cells.

This may help to explain why sporadic ALS, without a known genetic cause, can spread systematically from region to region of the body in a progressive manner. While ALS is predominantly sporadic, it is associated with heritable genetic mutations in 5% to 10% of cases, including those in SOD1.

“If it is established that misfolding of SOD1 is indeed propagated between cells in human ALS patients, then immunotherapies to block this process may arrest the disease,” Cashman explains. “There is also evidence that extracellular misfolded SOD1 is toxic for neurons, and this toxicity may be neutralized by immunotherapies as well.”

Cashman says pharmaceutical agents could be designed to inhibit cell-to-cell spread of protein misfolding when the process by which release and uptake of misfolded SOD1 is better understood. He adds that programs are under development for SOD1 immunotherapies at companies worldwide, including Biogen-Idec Corp, but says Biogen is still 3 years away from clinical trials with this novel treatment modality.

Meanwhile, Cashman and his colleagues plan to continue take their research to the next level. “We will advance with our antibodies into mouse models, which will capture the cell-to-cell spread of misfolded wild-type SOD1,” he says.

—Colleen Mullarkey

Reference

Grad LI, Yerbury JJ, Turner BJ, Guest WC, Pokrishevsky E, O’Neill MA, et al. Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and -independent mechanisms. Proc Natl Acad Sci U S A. 2014 Feb 18. [Epub ahead of print].