Researchers Map Immune Molecule Behavior in Affected Motor Neurons

Immune-related molecules change in motor neurons affected by amyotrophic lateral sclerosis (ALS), but they do not appear to be major drivers of disease progression. The findings, published by researchers at Stockholm University, provide new mechanistic insights into disease pathology in ALS.

One of the central questions in ALS is why some motor neurons die while others survive. Our study examined whether immune-related molecules could explain this selective vulnerability, but we found that they are only one small piece of a much larger puzzle." 

Eva Hedlund, Professor, Stockholm University

The researchers focused on the major histocompatibility complex I (MHC-I), a group of molecules best known for their role in the immune system but also important for normal nervous system function. Previous studies have suggested that reduced levels of MHC-I components may make motor neurons more vulnerable in ALS.

Motor Neurons Try to Counteract Disease

The team found that the largest and most vulnerable spinal motor neurons naturally express lower levels of HLA, a key component of MHC-I. In tissues from ALS patients, HLA protein levels were reduced even further, while they remained preserved in disease-resistant oculomotor neurons that control eye movements.

While HLA protein levels declined, ALS spinal motor neurons increased their mRNA expression of certain HLA transcripts and of β2-microglobulin (β2m), another pivotal component of MHC-I. This indicates an attempted compensatory response that fails to restore protein levels.

"The findings suggest that vulnerable motor neurons actively try to counteract disease-associated stress but that this response is ultimately insufficient," says Dr Melanie Leboeuf, the study's first author.

*Human leukocyte antigens (HLAs) are cell-surface proteins that present peptides to T cells, enabling the immune system to distinguish healthy cells from infected or abnormal cells.

*Beta-2 microglobulin (β2m) are small proteins found on the surface of most cells in the body, helping the HLA proteins to work properly. Together HLAs and b2m constitute the so-called MHC-I complex.

A Complex Disease Process

To investigate whether β2m influences disease progression, the researchers removed the gene in a mouse model of ALS. The researchers found that deleting β2m helped preserve nerve connections to specific muscles, but the effect was limited and did not improve overall motor function or lifespan of the mice. Unexpectedly, the team discovered that mice lacking the β2m gene exhibited marked astrocyte activation, even in the absence of motor neuron disease.

*Astrocytes are cells in the nervous system that play an activate role in ALS and appear to attack motor neurons in the disease.

Loss of β2m also resulted in further increased astrocyte activation in ALS mice, yet without worsening disease progression. This suggests that β2m normally contributes to regulating astrocyte reactivity. It also demonstrates that activation of astrocytes alone is insufficient to drive motor neuron degeneration, even when neurons lack functional MHC-I on their surface. It also suggests that once a threshold in astrocyte activation is reached, further reactivity does not exacerbate disease.

"We found that beta2-microglobulin clearly influences how motor neurons and their environment respond to disease yet removing it had remarkably little effect on overall disease progression. That tells us it is not a major disease modifier in ALS," says Melanie Leboeuf.

The findings show that while MHC-I-related molecules are dynamically regulated in ALS, they are unlikely to be key drivers of disease progression. Instead, they appear to represent one small part of a much more complex disease process, providing researchers with a clearer picture of the biological mechanisms underlying ALS.