Related Experiment Video
Updated: Sep 28, 2025
Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Survival motor neuron protein deficiency alters microglia reactivity
Guzal Khayrullina1, Zaida A Alipio-Gloria2, Marc-Olivier Deguise3,4,5,6
1Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, F. Edward Hebert School of Medicine, Bethesda, Maryland, USA.
Abstract:
Survival motor neuron (SMN) protein deficiency results in loss of alpha motor neurons and subsequent muscle atrophy in patients with spinal muscular atrophy (SMA). Reactive microglia have been reported in SMA mice and depleting microglia rescues the number of proprioceptive synapses, suggesting a role in SMA pathology. Here, we explore the contribution of lymphocytes on microglia reactivity in SMA mice and investigate how SMN deficiency alters the reactive profile of human induced pluripotent stem cell (iPSC)-derived microglia. We show that microglia adopt a reactive morphology in spinal cords of SMA mice. Ablating lymphocytes did not alter the reactive morphology of SMA microglia and did not improve the survival or motor function of SMA mice, indicating limited impact of peripheral immune cells on the SMA phenotype. We found iPSC-derived SMA microglia adopted an amoeboid morphology and displayed a reactive transcriptome profile, increased cell migration, and enhanced phagocytic activity. Importantly, cell morphology and electrophysiological properties of motor neurons were altered when they were incubated with conditioned media from SMA microglia. Together, these data reveal that SMN-deficient microglia adopt a reactive profile and exhibit an exaggerated inflammatory response with potential impact on SMA neuropathology.
Insights
Spinal muscular atrophy (SMA) involves SMN protein deficiency. This study shows SMN-deficient microglia become reactive, impacting motor neurons and potentially contributing to SMA neuropathology.
Area of Science:
- Neuroscience
- Immunology
- Stem Cell Biology
Background:
- Spinal muscular atrophy (SMA) is characterized by Survival Motor Neuron (SMN) protein deficiency, leading to motor neuron loss and muscle atrophy.
- Reactive microglia are implicated in SMA pathology, but the specific role of lymphocytes and the intrinsic reactivity of SMN-deficient microglia remain unclear.
Purpose of the Study:
- To investigate the contribution of lymphocytes to microglial reactivity in SMA mice.
- To characterize the reactive profile of human induced pluripotent stem cell (iPSC)-derived microglia with SMN deficiency.
- To assess the impact of SMN-deficient microglia on motor neuron health.
Main Methods:
- Analysis of microglial morphology in SMA mouse spinal cords.
- Lymphocyte ablation in SMA mice.
- Generation and characterization of iPSC-derived microglia from SMA patients.
- Transcriptome analysis of iPSC-derived microglia.
- Cell migration and phagocytosis assays.
- Incubation of motor neurons with conditioned media from SMA microglia.
Main Results:
- Microglia exhibit reactive morphology in SMA mouse spinal cords.
- Lymphocyte ablation did not affect SMA microglia reactivity or mouse phenotype.
- iPSC-derived SMA microglia showed amoeboid morphology, a reactive transcriptome, increased migration, and enhanced phagocytosis.
- Conditioned media from SMA microglia altered motor neuron morphology and electrophysiology.
Conclusions:
- SMN-deficient microglia display an intrinsic reactive profile and exaggerated inflammatory response.
- Peripheral lymphocytes have a limited impact on microglial reactivity and SMA phenotype.
- SMN-deficient microglia may directly contribute to SMA neuropathology through inflammatory mechanisms affecting motor neurons.
