New Disease Pathway Identified for ALS

Packard scientists discover that blocking a key molecule of inflammatory pathway may one day lead to better treatments.

Researchers at Laval University in Quebec, led by Packard Center scientist Jean-Pierre Julien, have discovered that two key proteins may act together to help cause some of the symptoms of ALS. Although researchers had previously linked one of these proteins to ALS (TDP-43), this is the first time its partner in crime – a protein known as nuclear factor- kappa B (NF-kB) – has been tied to ALS. NF-kB is a key regulator for the synthesis of a number of factors associated with innate immunity and inflammation. Together, researchers say, these new findings may point to a potential new therapeutic target for ALS.

“This is very new. I was very surprised myself when I first saw the results,” Julien said. “NF-kB is a key molecule. It was surprising to me that this protein can be activated in motor neurons. I did not expect it.” This study is the first time that NF-kB has been linked to ALS.

In 2006, researchers showed that the majority of ALS patients had cytoplasmic aggregates composed of an RNA-binding protein known as TDP-43. Mutations in the TAR-DBP gene, which codes for TDP-43, have been discovered in ALS patients. Subsequent studies have linked variations in another RNA-binding protein, called FUS, to ALS. In ALS patients, these mutant proteins glob together in the cytoplasms of motor neurons and associated cells.

Julien and his colleagues found evidence that TDP-43 interacts with p65, a small piece of NF-kB, in the spinal cords of ALS patients but not in healthy subjects. They also report that higher levels of TDP-43 and of p65 were detected in the spinal cords of ALS patients. Such elevation in levels of TDP-43 was found to enhance the p65 activity resulting in exaggerated inflammatory responses in immune cells. This can lead to the production of soluble molecules and factors that lead to enhanced toxicity toward neighboring cells.

Activation the inflammatory NF-kB pathway was also detected within ALS motor neurons and found to enhance their vulnerability to toxic mediators. The researchers found that TDP-43 and p65 work in tandem to increase many inflammatory chemicals in the spinal cords of ALS patients. When Julien and his co-workers administered a drug that blocked the action of p65 in a mouse model of ALS, they found that it decreased both the pathological features and the symptoms of ALS.

“The good news for ALS patients is that therapeutic interventions to target this pathway is conceivable. However, we must keep in mind that NF-kB inhibitors will have to be tested cautiously to not compromise too much healthy immune responses. Indeed, we have an ongoing project supported by the Packard Center to develop a therapeutic approach that can target specifically the interaction between TDP43 and NF-kB p65,” Julien said.