Lack of SMN May Make Brain Immune Cells More Prone to Promoting Inflammation
Loss of the survival motor neuron (SMN) protein changes the function of a type of brain immune cell called microglia, making them more prone to promoting inflammation and disease progression in spinal muscular atrophy (SMA), a new study reveals.
The study, “Survival motor neuron protein deficiency alters microglia reactivity,” was published in the journal GLIA.
Microglia are the primary immune cells found in the central nervous system (CNS, comprising the brain and spinal cord). They protect neurons from harmful organisms and other threats by releasing inflammatory proteins, recruiting lymphocytes (specialized immune cells), and clearing dead cells and waste material.
SMA is characterized by deletions or mutations in the SMN1 gene, leading to reduced production of the SMN protein and progressive muscle weakness and deterioration. Although microglia typically play a protective role, it is unclear if SMN deficiency affects their functioning. Past studies in mouse models of the disease have also shown that lymphocyte numbers are increased, but it is unknown whether they contribute to the progression of the disease.
Now, a team of scientists investigated whether SMN deficiency affects microglia functioning. They also investigated if lymphocytes contribute to disease progression in SMA. The study was done using a mouse model of SMA and cell cultures of microglia derived from patients with SMA.
Compared with microglia from control mice, those from SMA mice had altered structures consistent with activation and increased expression of inflammatory proteins. Microglia derived from patients with SMA also displayed similar structural changes, indicating activation.
Patient-derived microglia had higher expression of genes regulating the production of inflammatory proteins such as cytokines and chemokines, compared with control microglia. There was also increased expression of the genes involved in regulating microglia shape, movements to sites of inflammation, and phagocytosis — the process of eliminating harmful agents or dead cells. Gene expression is the process by which information in a gene is synthesized to create a working product, like a protein.
Moreover, the higher expression of these genes correlated to increased phagocytosis and migration of SMA-derived microglia compared to control microglia. Although it is known that microglia migrate to and adopt a more inflammatory-prone profile at the site of neuronal loss in SMA mice models, what exactly triggers this migration is not known.
SMA-derived microglia were also shown to produce various factors that alter the excitability of motor neurons, promoting disease progression.
“We show that SMA microglia not only display enhanced phagocytic activity but release factors that alter motor neuron morphology and electrical properties…This is a novel finding as it shows that microglia in SMA have conflicting effects on motor neuron physiology,” the researchers wrote.
While lymphocytes are known to migrate into the CNS in various neurological conditions, no evidence was found of increased lymphocyte movement into the CNS in the SMA mouse model. Depleting lymphocytes, both B and T cells, did not improve muscle function or disease progression in this model either, suggesting that lymphocytes do not affect microglia function in SMA.
“Importantly, we show that the reactive profile of SMA microglia is unaltered by loss of lymphocytes,” the researchers wrote.
Further studies are needed to determine the various roles of microglia in SMA.
“Overall, we have shown that loss of lymphocytes does not improve SMA disease phenotype and likely does not contribute to the microglia phenotype in SMA mice. SMN-deficient microglia displayed an altered [gene] profile, increased mobility and enhanced phagocytic activity, which could modify the SMA phenotype,” the researchers concluded.