Interplay of Motor Neurons and Glial Cells at Root of SMA, Review Suggests

The interplay between different types of nerve cells, including motor neurons and glial cells, seems to be at the root of motor neuron degeneration and denervation, or the loss of nerve supply, that characterizes spinal muscular atrophy (SMA), a review study reports.

The study, “Glial cells involvement in spinal muscular atrophy: Could SMA be a neuroinflammatory disease?” was published in the journal Neurobiology of Disease.

SMA is characterized by the gradual loss of motor neurons — the nerve cells responsible for controlling voluntary muscles — in the spinal cord, leading to muscle weakness. It is caused by mutations in the SMN1 gene, which provides instructions to make the SMN protein that is essential for motor neuron survival.

Although SMA is considered a motor neuron disease, evidence from recent studies suggests that other types of nerve cells may also be involved in its development. These include glial cells, the most abundant cell type found in the central nervous system (CNS; comprising the brain and spinal cord), and responsible for providing protection and support to neurons.

“Although … motoneuronal toxicity in this disease has been established, growing evidence supports the possibility that, in addition to that, glial dysfunction and glial-mediated inflammation might be able to compromise neuronal survival and promote progression and propagation of the degenerative process,” the researchers wrote.

Their review study focused on summarizing the main findings of different studies investigating the possible contribution of different types of glial cells, including astrocytes, microglia, oligodendrocytes, and Schwann cells, for the development of SMA.

Microglia are considered the ‘sentinel’ immune cells of the CNS, whose main function is to protect neurons from microbes or other threats. Astrocytes are star-shaped cells that provide nourishment to neurons, and are also important for their maturation and differentiation. Like microglia, astrocytes can respond to pro-inflammatory signals released by immune T-cells, contributing to neuroinflammation.

Oligodendrocytes are the glial cells in the CNS that are responsible for producing myelin — the fatty substance that wraps around nerve segments, or axons, to ensure the transmission of nerve cell impulses. Like oligodendrocytes, Schwann cells also produce myelin. However, while oligodendrocytes are found in the CNS, Schwann cells are only present in the peripheral nervous system (PNS), which includes all nerves found outside the brain and spinal cord.

In other neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease, microglia and astrocytes are thought to either work in concert, or sequentially, to promote immune and inflammatory responses. Their chronic activation is also thought to lead to the production of toxic reactive oxygen species (ROS) that contribute to oxidative stress (cell damage caused by high levels of toxic oxidant molecules) and neurodegeneration.

Oligodendrocyte dysfunction has also been reported in other neurological diseases, including Parkinson’s disease and multiple system atrophy (MSA). Such problems in the working of oligodendrocytes may also lead to neuron death due to the activation of neuroinflammatory signaling cascades, along with the loss of support provided by these cells.

Studies in SMA animal models have identified several abnormalities in the function of astrocytes. For instance, it has been reported that the lack of SMN protein associated with SMA affects the interaction between motor neurons and astrocytes, and their ability to form functional synapses, or the sites where nerve cells communicate.

In contrast, restoring SMN protein levels in astrocytes has been shown to prolong the lifespan and ameliorate motor function of mice with SMA, while also rescuing defects in synapses and neuromuscular junctions (NMJs; the sites where nerve and muscle cells communicate). Other studies also reported the presence of astrogliosis — a phenomenon in which the number of reactive astrocytes increases dramatically due to the loss of nearby neurons — in mice with end-stage SMA, as well as in post-mortem patient tissue samples.

Changes in microglia function have also been reported in animals models of SMA. Some of these findings included the presence of microgliosis in association with astrogliosis around motor neurons, and microglia activation in the spinal cord of mice with SMA. Similarly to astrogliosis, microgliosis refers to the process through which the number of microglia increases substantially in response to an injury; microglia activation is the process by which microglia become overactive, triggering inflammation.

Abnormalities in the function of Schwann cells have also been described in several studies using different SMA models.

“It has been recently reported that low levels of SMN in Schwann cells are able to trigger changes leading to abnormal axonal myelination … [and that] the selective genetic correction of SMN levels in Schwann cells reverted myelination defects, improved neuromuscular function and ameliorated neuromuscular junction pathology [disease] in SMA mice,” the researchers wrote.

Studies reporting the possible involvement of oligodendrocytes in SMA are more scarce. However, a recent study reported defects in the differentiation and function of cells belonging to the lineage of oligodendrocytes isolated from SMA mice and from patients’ induced pluripotent stem cells (iPSCs).

Of note, iPSCs are fully matured cells that can be reprogrammed back to a stem-cell state, from which they are able to grow into almost any type of cell.

“From all the studies discussed so far, it emerges that SMA is [a multifactorial] disease in which glial cells and motor neurons influence each other and contribute to denervation, synaptic loss and eventually cell death,” they wrote.

“Several mechanisms seem to be implicated in this glial-mediated damage, and many are probably still obscure. Nonetheless, from our discussion it emerges as a prominent culprit the disruption in different neuronal-glial interactions, such as synapse formation and remodeling, intercellular transmission and myelination.”

A “deeper characterization of these processes in SMA is warranted, not only for a better understanding of the pathogenic mechanisms, but also for a refinement of our therapeutic weapons,” the researchers concluded.