SMN-deficient microglia may play a complex role in the pathology of spinal muscular atrophy (SMA), according to a new study published in Glia.
Human-induced pluripotent stem cell (iPSC)-derived microglia obtained from a patient with SMA exhibited a reactive morphology with an increased soma size and reduced number of processes and an altered transcriptome profile compared to control iPSC-derived microglia.
The SMA microglia also had increased cell migration velocity and phagocytic activity. Reactive morphologies of microglia were also observed in the spinal cords of an SMA mouse model.
SMN-deficient and control iPSC motor neurons had increased levels of evoked action potentials when incubated in media conditioned by SMA microglia when compared to media from wild-type microglia. The SMN-knockdown neurons also showed increased sodium and potassium currents when exposed to the SMA-conditioned media.
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The morphology of the motor neurons was also affected by the media conditioned by SMA microglia and displayed increased neurite branching and enhanced extension. These results highlight the effect of the SMA microglial secretome as well as the responsiveness of SMN-depleted motor neurons to those signals.
“Together, we show that factors released by SMA microglia alter both the morphology and electrophysiological properties of motor neurons, further implicating glia in SMA pathology,” the authors said.
The researchers also found that lymphocytes do not appear to play a major role in SMA pathology. In some neurodegenerative disorders including amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease, lymphocytes have been observed to infiltrate the central nervous system and activate microglia.
In the current study, neither CD4 (Smn2B/−;CD4−/−) nor RAG1 (Smn2B/−;Rag1−/−) knockout mice lacking SMN showed improvement in motor function, weight, or survival compared to Smn2B/− controls. Loss of lymphocytes through the knockout of RAG1 also did not affect the reactive morphology of SMA microglia.
“Further studies using iPSC-derived microglia and neuron co-cultures will be critical in establishing the different roles of microglia in SMA disease pathology,” the authors said. These results suggest that lymphocytes do not substantially contribute to the pathophysiology of SMA.
Khayrullina G, Alipio-Gloria ZA, Deguise MO, et al. Survival motor neuron protein deficiency alters microglia reactivity. Glia. Published online April 4, 2022. doi:10.1002/glia.24177