Newswise \u2014 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.<\/p>\n
\u201cOne 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,\u201d says Professor Eva Hedlund, who led the study together with Professor Staffan Cullheim at Karolinska Institutet.<\/p>\n
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.<\/p>\n
Motor neurons try to counteract disease<\/p>\n
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.<\/p>\n
While HLA protein levels declined, ALS spinal motor neurons increased their mRNA expression of certain HLA transcripts and of \u03b22-microglobulin (\u03b22m), another pivotal component of MHC-I. This indicates an attempted compensatory response that fails to restore protein levels.<\/p>\n
\u201cThe findings suggest that vulnerable motor neurons actively try to counteract disease-associated stress but that this response is ultimately insufficient,\u201d says Dr Melanie Leboeuf, the study’s first author.<\/p>\n
*Human leukocyte antigens (HLAs)\u00a0are cell-surface proteins that present peptides to T cells, enabling the immune system to distinguish healthy cells from infected or abnormal cells.<\/p>\n
*Beta-2 microglobulin (\u03b22m)\u00a0are 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.<\/p>\n
A complex disease process<\/p>\n
To investigate whether \u03b22m influences disease progression, the researchers removed the gene in a mouse model of ALS. The researchers found that deleting \u03b22m 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 \u03b22m gene exhibited marked astrocyte activation, even in the absence of motor neuron disease.<\/p>\n
*Astrocytes\u00a0are cells in the nervous system that play an activate role in ALS and appear to attack motor neurons in the disease.<\/p>\n
Loss of \u03b22m also resulted in further increased astrocyte activation in ALS mice, yet without worsening disease progression. This suggests that \u03b22m 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.<\/p>\n
\u201cWe 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,\u201d says Melanie Leboeuf.<\/p>\n
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.<\/p>\n