Cell Death Protein Marks Vulnerable Nerve Cells in 2 SMA Mouse Models
The elevated production of the cell-death-related protein c-Fos was closely linked to the death of motor neurons in two mouse models of spinal muscular atrophy (SMA), a study showed. Motor neurons are the muscle-controlling nerve cells that are lost in people with SMA.
Although c-Fos didn’t directly cause the motor neurons’ death, and is therefore not suitable as a therapeutic target in SMA, it appeared to be a selective marker for vulnerable motor neurons and may be a valuable readout when evaluating new therapeutic approaches, researchers said.
The study, “p53-dependent c-Fos expression is a marker but not executor for motor neuron death in spinal muscular atrophy mouse models,” was published in Frontiers in Cellular Neuroscience.
Motor neurons die in SMA as a result of an inherited deficiency in the SMN protein. Although SMN is found in most cells in the body, motor neurons appear to be especially vulnerable to its deficiency.
The tumor suppressing protein p53 plays a crucial role in preventing cells from becoming cancerous. It detects DNA damage and activates genes to either repair the DNA or, when there is too much damage, to trigger cell death to prevent abnormal cells from growing.
Evidence suggests the abnormal production of p53 selectively drives the death of motor neurons in SMA. But its blockade is not a therapeutic option due to the risk of cancer.
Research into potential target genes of cell death
Instead, researchers at Leipzig University, Germany, investigated potential target genes of p53-mediated cell death, including c-fos, perp, and fas, in vulnerable motor neurons of a severe SMA mouse model.
Motor neurons in spinal cord sections at the base of the spine (L1) were examined at four days after birth (P4), when motor neuron death is at its peak in this model, and 10 days after birth (P10), with little or no motor neuron death.
Compared with healthy mice, the activity of perp and fas genes was elevated in SMA mice at P4, but continued to rise at P10, “when the process of L1 motor neuron death is already completed,” the researchers wrote.
In turn, c-fos gene activity was strongly increased at P4 but dropped to normal levels at P10, demonstrating that only c-fos “timely correlates with motor neuron death in a severe SMA mouse model,” they said.
Consistently, c-Fos protein levels increased significantly at one day after birth, peaked at P4, and dropped to levels comparable to healthy mice at day 10 after birth in vulnerable SMA motor neurons.
In resistant pools of motor neurons, c-Fos protein levels remained comparable to those of healthy mice at all evaluated time points.
“These results reveal a strong correlation of the amount of c-Fos upregulation and occurring motor neuron death in vulnerable SMA motor neuron pools,” the researchers wrote.
Cause of c-Fos upregulation, effect on motor neurons
To test whether elevated c-Fos was due to p53 activation, mice with severe SMA-like disease were treated with PFT, a chemical that blocks p53’s ability to activate other genes. PFT exposure prevented the death of motor neurons without altering p53 production.
Blocking p53 with PFT significantly decreased c-Fos protein levels relative to untreated SMA mice. At the same time, PFT didn’t affect c-Fos in normal mice, together demonstrating “c-Fos upregulation in SMA is indeed p53-dependent,” the researchers wrote.
Although elevated c-Fos levels appeared to mark vulnerable motor neurons in the severe SMA mouse model, the researchers also wanted to know if c-Fos also caused motor neuron death and could be a potential therapeutic target.
They deleted the c-fos gene selectively from motor neurons of the mouse model. This deletion neither delayed nor prevented motor neuron death in the animals nor did it alter the number of motor neurons in otherwise healthy mice. Also, a lack of c-fos didn’t improve motor function or the abnormal structure and function of the neuromuscular junction where motor neurons connect with the muscles they control.
“Taken together, these results demonstrate that c-Fos does not mediate motor neuron death in SMA mice,” the research team wrote.
Finally, to explore whether c-Fos activation in vulnerable motor neurons occurs in different types of SMA, the team measured c-fos gene activity in a mouse model of an intermediate form of SMA. In these mice, L1 motor neuron death happens at a late stage, by 27 days after birth.
Up to day 22 after birth, c-fos activity in the motor neurons of the intermediate SMA mouse model was similar to control levels. By day 27, c-fos activity doubled, with no change observed in non-motor neuron cells, which associates “c-Fos upregulation with the death of vulnerable motor neurons in this SMA mouse model,” the researchers wrote.
PFT treatment confirmed c-fos activity was p53-dependent in the intermediate SMA mouse model, as in the severe SMA model.
“Taken together, p53-dependent [production] of c-Fos marks degenerating motor neurons of different SMA mouse models,” the researchers wrote, adding that the cell death-related protein could be used as a “potential diagnostic readout in SMA and possibly “other p53-associated neurodegenerative diseases.”
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