New findings on spinal muscular atrophy

Spinal muscular atrophy (SMA) is a neurodegenerative disorder that leads to muscle loss and can severely impair the mobility of those affected. It is usually caused by a defect in the SMN1 gene, which is expressed in all cells of the body. Whether this mutation also affects the immune system remains largely underexplored. That is precisely what researchers from TWINCORE, the Centre for Experimental and Clinical Infection Research, and Hannover Medical School (MHH) have now investigated. Their findings have been published in the Journal of Clinical Investigation.

In patients with SMA, a mutation in the SMN1 gene usually results in reduced levels of functional Survival of Motor Neuron (SMN) protein. This causes motor neurons to die off, preventing muscle cells from being properly stimulated and ultimately leading muscle atrophy. As a result, people with SMA suffer from severe motor impairments. Without treatment, the life expectancy of patients with a severe form of SMA can be significantly reduced. Three different drugs are approved for the treatment of SMA in Germany. They compensate for the SMN deficiency and can thus alleviate the symptoms of SMA.

However, the SMN protein is not restricted to cells of the nervous system but is found throughout the body. “We were interested in whether and how the cells of the immune system are affected in people with SMA,” says Dr Ines Tapken, one of the study’s two lead authors. She conducted research into SMA during her PhD and as a postdoctoral researcher at the MHH. “We therefore examined the immune cells in the blood of patients with SMA, both with and without drug therapy, and compared them with those of healthy controls.”

To do this, the researchers isolated the so-called peripheral blood mononuclear cells (PBMCs) and characterised them in more detail using spectral flow cytometry. “We analysed both the composition of the immune cell populations and measured the amount of SMN protein in individual cell types,” says the other lead author, Katharina Rahmel-Stein, a PhD student at the Institute for Experimental Infection Research at TWINCORE. “It was particularly striking that, in healthy controls, monocytes and dendritic cells exhibited comparatively higher SMN levels.” At the same time, the overall composition of the immune cell populations in patients with SMA differed from that of healthy controls.

In addition to the human patients, Tapken and Rahmel-Stein also examined immune cells from the spleen of mice with SMA. Pronounced alterations were already apparent in three-day-old animals. “This can probably be attributed to the fact that in mice, the SMN protein also plays a role in cell differentiation during embryonic development,” says Tapken. “A direct comparison with conditions in humans is therefore not possible, but important mechanistic conclusions can be drawn from the mouse experiments.”

“Even though there is currently only limited clinical evidence that SMA is associated with functional alterations of immune cells, our analyses have shown that all cell types express less SMN. And this applies equally to patients with SMA and to the SMA mouse model,” says Rahmel-Stein. “We suspect that long-term SMN deficiency could impair the human immune system later in life.” This could be the focus of future studies to help us broaden our understanding of SMA beyond its neurological manifestations.

In addition to other groups from MHH, Essen University Hospital and the University of Naples, Dr Dr Theresa Graalmann and Dr Christine Ehlers from the Junior Research Group Clinical Immunology at TWINCORE were also involved in the study.