Certain motor neurons resistant to degeneration in SMA: Study
Neuron degeneration patterns could provide clues to new therapeutic targets
While certain populations of motor nerve cells — and the muscles they connect to — are vulnerable to degeneration in spinal muscular atrophy (SMA), others appear resistant to this damage, a study found.
Similar patterns were observed when looking at tissue from patients with SMA type 1 and a mouse model of SMA.
Further study of these resistant populations could help identify new therapeutic targets for preserving muscle function in SMA, the researchers said. The study, “Motor pool selectivity of neuromuscular degeneration in type I spinal muscular atrophy is conserved between human and mouse,” was published in Human Molecular Genetics.
SMA is caused by mutations in the SMN1 gene that lead to a lack of functional SMN protein. SMN is found throughout the nervous system, but its loss in SMA selectively affects the specialized nerve cells involved in coordinating voluntary movements, called motor neurons. Consequently, motor neurons progressively degenerate, leading to symptoms of muscle weakness and wasting (atrophy).
Some studies indicate that certain subpopulations of motor neurons are more vulnerable to a lack of SMN and degenerate more readily, leading to more severe wasting of the muscles they communicate with (innervate). Others are more resistant, and the muscles they innervate are preserved. For example, oculomotor nerves, which innervate eye muscle, tend to be preserved in SMA, and SMA patients don’t usually have problems with eye movements.
Neuron degeneration
To learn more about how different motor pools (a group of neurons that innervate a single muscle) and their corresponding muscles are affected in SMA, the scientists studied neuromuscular autopsies from 10 infants with SMA type 1, a severe form of the disease with an onset in infancy, and one infant without SMA who died due to an unrelated cause.
In general, widespread motor neuron loss was observed in the SMA tissue, particularly in the spinal cord and certain cranial motor nerves, which control movements in the head and neck.
There was a high degree of variability in the degree to which motor pools and their corresponding muscles were affected.
For example, oculomotor nerves and the extraocular muscles they innervate were relatively spared, consistent with previous observations.
The intercostal and rectus abdominal muscles, both of which are found in the trunk of the body and are involved in breathing, showed a moderate degree of atrophy. The diaphragm, another important breathing muscle, and the phrenic nerve that innervates it were largely spared from damage.
To examine the long-term preservation of muscles in SMA, the scientists examined tissue from a SMA type 1 patient who had survived on respiratory support until age 17. While many muscles were severely degenerated, as would be expected, the diaphragm, “remarkably,” was spared, they said.
The scientists also looked to see whether there were particular motor unit characteristics associated with vulnerability versus resistance in SMA.
Position didn’t seem to make much of a difference. Motor pools lying near each other in the spinal cord showed different degrees of damage.
The scientists did find, however, that all the motor pools that appeared resistant to damage, such as ones involved in eye movements, had high activity levels.
But even among resistant muscles, there was evidence of molecular changes indicating some degree of degeneration might be happening, even if it wasn’t enough to cause those muscles to be dysfunctional.
Several of the characteristics observed in the human SMA tissue were paralleled in a commonly used mouse model of SMA. That “provides rationale for its use as a preclinical model … and suggests that mechanistic conclusions drawn from its study may be relevant in human patients,” the researchers wrote.
All approved SMA disease-modifying therapies work in various ways to increase SMN production. The study data show new pathway for identifying treatments that work independently of increasing SMN, the researchers said. For example, they said, if scientists can identify why certain motor neurons are so resistant, they can leverage those mechanisms to preserve other more vulnerable cells.
“Mechanisms that confer selective resistance to SMA may represent therapeutic targets independent of the SMN protein, particularly in patients with neuromuscular weakness refractory [resistant] to current treatments,” the researchers wrote.
About the Author
