The nerve cells of some people with the serious disorder amyotrophic lateral sclerosis can accumulate clumps of a protein called SOD1. A mutation in the SOD1 gene is known to cause the disease, but it has not been clear if the characteristic clumps of the protein associated with the faulty gene are active drivers or harmless byproducts of the disease. Now, a new study suggests they are drivers.

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The researchers suggest aggregated SOD1 protein likely drives ALS. It is seen here green dots in the fluid of a nerve cell in the spinal cord of an ALS patient – with the nerve cell nucleus highlighted in red.
Image credit: Peter Andersen/Umeå University

The new study – by Umeå University in Sweden and published in the Journal of Clinical Investigation – finds that when injected into mice, SOD1 protein aggregates spread rapidly, leading to amyotrophic lateral sclerosis (ALS).

The authors note that while researchers have known about SOD1 aggregates in nerve cells in ALS patients for a while, it was not clear what role they played in people carrying the faulty gene.

Thomas Brännström, co-author and professor of pathology, explains what they found:

“We have now been able to show that the SOD1 aggregates start a domino effect that rapidly spreads the disease up through the spinal cord of mice. We suspect that this could be the case for humans as well.”

ALS, also known as Lou Gehrig’s disease after the well-known baseball player who first brought it to public awareness, destroys motor neurons – the nerve cells that control muscle movement – in the brain and spinal cord.

The disorder brings on progressive paralysis and death, and most patients only live 2-5 years after diagnosis. There are rare exceptions, including the famous theoretical physicist Stephen Hawking, who was diagnosed with ALS over 50 years ago.

The team identified two different kinds (called A and B strains) of SOD1 aggregates in mice – both of which spread when injected into the animals’ spinal cords. The protein clumps spread in nerve cells along the whole spinal cord, coincident with progression of an ALS-like disease that resulted in death.

For their study, the team used mice genetically modified to carry the human form of the SOD1 gene. The authors note:

“Mice seeded with A or B aggregates developed premature signs of ALS and became terminally ill after approximately 100 days, which is 200 days earlier than for mice that had not been inoculated or were given a control preparation.”

They also note how at the same time, aggregations of both A and B strains of human SOD1 protein propagated throughout the spinal cord and brainstem. Progression rates, distribution and levels of aggregation at the end stage, plus the disease patterns in the tissue, were different for A and B strains.

The researchers conclude that while the two strains of human SOD1 protein aggregates are different, they appear to “spread disease in a prion-like fashion” throughout the central nervous system, resulting in a “fatal ALS-like disease.”

Prions are toxic, misshapen proteins that copy themselves and travel along brain networks, clogging up cells along the way. This mechanism has been proposed for other neurodegenerative disorder, such as Alzheimer’s disease and bovine spongiform encephalopathy (BSE – commonly known as mad cow disease).

Another of the researchers, Stefan Marklund, professor of clinical chemistry, concludes their study strongly suggests SOD1 aggregation plays an important role in the progression of ALS, something he and his colleagues at Umeå have suspected for some time.

More research is necessary, but our aim is to develop interventions that prevent or stop the fatal course of the disease in carriers of hereditary traits of ALS.”

Prof. Stefan Marklund

Learn how another protein called FUS appears also to be involved in killing nerve cells in ALS.