A recent paper from French researchers questions one of the primary ideas about what causes amyotrophic lateral sclerosis (ALS), and proposes that over-active nervous system cells are not a primary cause of the neurodegenerative disease. The paper, titled “Is hyperexcitability really guilty in amyotrophic lateral sclerosis?” appeared in the journal Neural Regeneration Research.
In ALS (also known as Lou Gehrig’s disease), nerve cells that control movement progressively die in the brain and spinal cord. This causes muscle weakness and paralysis, eventually affecting the ability to breathe. Unfortunately, there is no cure for the disorder, and very limited treatment options. Research into new possible treatments and ways of diagnosing the disease early are greatly needed. To facilitate treatments and diagnosis, a better understanding of the causes underlying ALS are necessary.
There are several hypotheses about what may cause ALS. Genetic factors, including abnormal proteins such as superoxide dysmutase (SOD), may underlie ALS neuron death. Although for years research has focused on SOD1 mutations as the main culprits involved in familial forms of ALS, researchers have discovered new genes without known functions that may also cause ALS. Several genes have been linked to the disease which is likely to be divided into multiple subtypes. The study authors noted that “C9ORF72, for example, is now recognized to account for 30% of the familial cases. Overall, ALS has been linked to 20 different genes, many also associated with other degenerative diseases (frontotemporal dementia, Alzheimer or ataxia).”
Another popular idea about ALS has to do with excessive levels of the neurotransmitter glutamate, caused by an abnormal entry of calcium into cells. This idea is known as “excitotoxicity,” meaning that neurons become overactive in the disease, leading to exhaustion and death. However, the authors are skeptical that this actually happens in ALS. Although initial studies showed that hyperexcitability occurs in the cells that control movement (motoneurons), more recent research has failed to demonstrate a link between over-active motoneurons and their eventual death.
In their study report, the researchers conclude “…intrinsic hyperexcitability is unlikely to lead to motoneuron degeneration in ALS since vulnerable motoneurons are not hyperexcitable…The fact that, in early stages, only the resistant motoneurons display hyperexcitability makes it unlikely that an initial phase of hyperexcitability during early development could trigger the late degeneration. The reason(s) why the largest adult motoneurons lose the ability to fire repetitively and whether this may lead to degeneration remains to be investigated.”
According to the researchers, more work is needed to fully understand how ALS motoneurons die. At present, current hypotheses may need revision and do not seem to be sufficient to explain the disease and how it develops.