Reevaluating the role of beta2-microglobulin: new insights on selective vulnerability in ALS pathology

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Amyotrophic lateral sclerosis (ALS) is characterized by the selective loss of motor neurons (MNs). Why these neurons are particularly vulnerable in ALS remains unclear, as does why certain MN groups remain resistant throughout the disease course. We investigated the role of the human leukocyte antigens (HLAs) and beta2-microglobulin (β2m) in MN susceptibility to ALS, given their reported involvement in both prolonging and shortening disease progression. Loss of HLAs in ALS has also been shown to increase MNs vulnerability to toxicity exerted by activated astrocytes. RNA sequencing of control tissues demonstrated that disease-resistant oculomotor neurons (OMNs) and Onuf's MNs exhibited β2m and HLA mRNA levels comparable to those of vulnerable spinal MNs, suggesting that baseline differences in these transcripts do not explain the differential vulnerabilities of these MN groups. However, HLA protein levels showed an inverse correlation with spinal MN size, with the large MNs, those lost early in ALS, displaying the lowest HLA expression. HLA protein levels were also reduced in spinal MNs from end-stage ALS patient tissues, while remaining relatively unchanged in OMNs. In contrast, spinal MNs uniquely exhibited significant upregulation of β2m and HLA-C transcripts during disease, likely reflecting a protective compensatory response. Together, these findings suggest that β2m and HLAs may contribute to spinal MN vulnerability in ALS. To assess their functional role, β2m knockout mice were crossbred with SOD1G93A ALS mice. Loss of β2m did not alter life span of the ALS mice, but led to partial preservation of lumbrical muscle innervation that was insufficient to maintain motor function. Analysis of GFAP immunoreactivity revealed marked neuroinflammation activation in the spinal cords of β2m knockout mice. As these mice retain normal MN numbers and life-span, this indicates that loss of functional MHC-I, even in the presence of astrocyte activation, is insufficient to cause MN disease. Furthermore, β2m knockout significantly increased GFAP activation in SOD1G93A mice, but did not further exacerbate disease progression, suggesting that loss of functional MHC-I does not necessarily render MNs more vulnerable to astrocyte toxicity. Overall, these findings indicate that β2m and HLAs are dynamically regulated in ALS, and may influence MN vulnerability, but they are not major disease modifiers in ALS.

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