Abstract: Spinal muscular atrophy(SMA) is an autosomal recessive neuromuscular disorder resulting from reduced Survival Motor Neuron(SMN) protein levels due to SMN1 mutations. SMA patients are categorized into types I-IV, who experience extensive spinal motoneuron (MNs) degeneration and death within weeks or years of birth. Current FDA-approved therapies via restoring SMN levels have limited effectiveness, suggesting an incomplete understanding of disease mechanisms. Recent evidence indicates that SMA could be systemic and developmental defects rather than postnatal spinal MN malfunction, with extrinsic influences from glial supportive cells that may contribute to disease onset and severity.
Astrocytes are key bioenergetic cells in the central nervous system(CNS) responsible for synthesizing and transporting lipid metabolites to fuel and detoxify neurons during development and homeostasis. Although astrocyte abnormalities are reported in SMA, the etiology and actions of astrocytes in SMA remain controversial, with undefined molecular mechanisms. Here, we have successfully established disease modeling by generating patient-specific neuromuscular organoids from induced pluripotent stem cells(iPSCs) derived from both healthy and different types of SMA patients, along with isogenic control, which are further benchmarked with human fetal datasets via Single-cell RNA sequencing analysis. Building on this, we found that SMA astrocytes exhibited varying degrees of developmental defects, which are highly associated with lipid metabolism deficiency, positively correlating with SMA severity. Furthermore, we identified reduced SREBF2 in SMA astrocytes., a key regulator for lipid metabolism responsible for cholesterol and fatty acids synthesis, which contribute to abnormal astrocyte formation and functional impairment, negatively impacting MN development and homeostasis, leading to increased disease susceptibility and reduced resilience. Restoring SMN cannot rescue deficient lipid pathways mediated by SREBF2 in both SMA astrocytes and SMA mouse models.
Our study revealed an SMN-independent disease mechanism and further research is warranted to explore whether restoring astrocytic SREBP2 could enhance therapeutic efficacy when combined with current treatment for SMA patients.
