Overactive signaling pathway linked to SMA cells’ recycling abnormalities
ERK pathway showed increased activity in patient cells, inhibiting it led to lower SMN protein levels
The overactivity of a specific signaling pathway may contribute to the abnormalities in clearing cellular waste that are commonly seen in spinal muscular atrophy (SMA), according to experiments with patient-derived cells.
This known cell survival pathway, dubbed the ERK signaling pathway, exhibited increased activity in the cells, while its inhibition led to decreased levels of the SMN protein that’s deficient in SMA and lowered markers of autophagy.
The role of ERK in SMA remains controversial, with some studies finding its activity to protect the motor nerve cells (neurons) that degenerate in SMA and others seeing deleterious effects, the researchers said.
Still, modulating the “ERK pathway may constitute a new strategy to target [motor neuron] degeneration,” they wrote in “ERK MAPK signaling pathway inhibition as a potential target to prevent autophagy alterations in Spinal Muscular Atrophy motoneurons,” which was published in Cell Death and Discovery.
The most common types of SMA are caused by mutations in the SMN1 gene, leading to a lack of functional SMN. While the molecular mechanisms underlying the process aren’t fully understood, SMN’s loss is associated with the progressive degeneration of nerve cells, called motor neurons, involved in voluntary movement.
Signaling pathway alterations important for nerve cell survival — such as the PI3K/Akt and ERK/MAPK pathways — may contribute to disease processes, according to scientists. In fact, studies have shown a reduced PI3K/Akt activation in SMA cells and increased ERK/MAPK activation in mouse SMA models and human SMA motor neurons.
Researching ERK activity in SMA
Researchers in Spain sought to better understand the possible role of these cell survival signaling pathways in SMA by examining motor neurons derived from an SMA patient and from a healthy person.
Inhibiting PI3K led to reduced SMN protein and SMN gene activity in both SMA and healthy cells. Likewise, inhibiting ERK signaling led to reduced SMN protein and gene activity in human cells and cells from an SMA mouse model, indicating PI3K and ERK are regulators of SMN.
The process through which cells recycle components that are faulty or no longer needed — called autophagy — is believed to be impaired in SMA. Because ERK activation is involved in this cellular recycling process, researchers looked at whether changes in this pathway could impact autophagy.
Markers of autophagy were significantly increased in SMA cells compared with control cells, but inhibiting ERK in the patient cells led to a significant marker reductions.
It’s been proposed that ERK over-activation in SMA cells may arise as a compensatory mechanism to prevent motor neuron death, given its role in cell survival. Its increase then could drive autophagy impairment, the researchers hypothesized. Still, the mechanisms by which ERK becomes overactive remain unclear.
When SMN levels were genetically increased in the cells, there was no change in markers of ERK activation, suggesting ERK overactivity is not a direct consequence of changes in SMN, but may be a secondary process, the researchers said.
However, when the scientists reduced calcium levels in the patient cells — which have been reported to regulate ERK activity — there was indeed a decrease in ERK activation along with reduced signs of autophagy.
As disrupted calcium signaling has been observed in SMA, and calcium modulation has been linked to changes in SMN protein levels and autophagy, changes in calcium levels could be a possible driver of ERK activation, the researchers said.
“Overall, these results suggest a connection between intracellular calcium levels and the activity of ERK signaling pathway, which in turn may regulate autophagy and SMN in SMA [motor neurons],” the researchers wrote, adding ERK activity’s exact role in SMA remains controversial. “Whether ERK over-activation is beneficial or deleterious in SMA disease is yet to be determined and can have diverse consequences.”