A blood sample from someone with amyotrophic lateral sclerosis could contain more than clues about how quickly the disease is progressing. It may also reveal an attempted defense against it.
Researchers in Japan found unusually high levels of a group of molecules called N-acyl taurines (NATs) in people whose ALS was progressing rapidly. At first glance, that might suggest the molecules were contributing to the disease.
But experiments that followed pointed in another direction. Increasing NAT-related signaling appeared to protect motor neurons, the nerve cells that control movement, in laboratory models of ALS. The findings raise the possibility that the body increases these molecules as part of an effort to limit the damage, even as the disease continues to worsen.
That unexpected relationship is what led the researchers to investigate whether strengthening the same pathway could have therapeutic potential.
The Blood Signal Tracked With ALS Progression
The team began by looking for metabolic differences between people with rapidly and slowly progressing ALS.
They analyzed blood samples and found that several NATs were elevated in patients with faster-progressing disease. The pattern was also reproduced in a separate group of patients, giving the researchers more confidence that the finding was not simply a quirk of the first sample.
Higher NAT levels were associated with a steeper decline on the revised ALS Functional Rating Scale, a measure used to track changes in abilities such as movement, speech, swallowing and breathing. The researchers also found a relationship between NAT levels and survival.
But those results could not answer the most important question: were the molecules helping ALS progress, or were they appearing because the body was responding to the disease?
To find out, the researchers moved beyond the blood samples.
Researchers Tried To Strengthen The Pathway
NATs belong to an expanded network of lipid signaling molecules that includes the endocannabinoid system, a group of chemical signals involved in processes including nerve activity and inflammation.
The researchers focused on an enzyme called fatty acid amide hydrolase (FAAH). One of its functions is to break down NATs. Blocking FAAH can therefore increase levels of NATs and related signaling molecules.
The team used a compound called PF-04457845, a potent FAAH inhibitor, in several ALS models. They tested it in genetically altered cells, motor neurons made from induced pluripotent stem cells derived from people with ALS, and mice carrying an ALS-associated SOD1 mutation.
The results were striking enough to support further investigation.
In the cell experiments, PF-04457845 improved the survival of ALS-associated motor neurons. In the mice, inhibiting FAAH increased NAT and related signaling in the spinal cord and was associated with less motor-neuron degeneration, slower loss of motor function, and longer survival.
The researchers also found changes involving the environment surrounding motor neurons, connections between nerve cells, and processes involved in neuronal development.
Why Higher NAT Levels May Not Be Bad
This is where the human blood results become particularly interesting.
Normally, finding higher levels of a biological molecule in people with a more aggressive disease might make researchers suspect that the molecule is harmful.
Here, the experiments suggest another possibility: NAT levels may rise as the nervous system attempts to protect itself.
If the body's response is too weak to stop ALS, patients with more severe or rapidly progressing disease could still have the highest NAT levels. The molecules would therefore be associated with worse outcomes without necessarily causing them.
The study does not prove that this is what happens in people. The blood analysis shows an association, while the evidence for a protective effect comes from laboratory and animal experiments.
That distinction is important when considering what the finding could mean for treatment.
A Potential Treatment Target, Not An ALS Drug Yet
PF-04457845 is not an established treatment for ALS, and the new research does not show that it can slow the disease in patients.
The compound has previously undergone human safety testing, but the ALS study tested its potential against the disease in cells and mice rather than in a clinical trial involving people with ALS. Whether the effects seen in those models translate to patients remains unknown.
Researchers will also need to determine how manipulating this pathway affects the human nervous system over longer periods and whether increasing NAT signaling can produce meaningful clinical benefits without causing unwanted effects.
For now, the most valuable part of the discovery may be the clue hidden in the blood itself.
A molecule that rises as ALS progresses is not necessarily a molecule driving the disease. It may be evidence of the nervous system trying to compensate for damage. If future research confirms that interpretation, strengthening that natural response could become a new direction in the search for treatments that do more than slow ALS by a modest amount.
