Assistant Professor City University of Hong Kong Hong Kong, Hong Kong
Abstract: Spinal muscular atrophy (SMA) is a leading inherited cause of infant and childhood mortality, caused by mutations in the gene encoding survival motor neuron(SMN) 1, resulting in reduced SMN protein levels. SMA patients experience progressive spinal motoneurons(MNs) degeneration, leading to declined motor functions and death within weeks or years of birth, depending on the severity of the disease. Despite three licensed SMA therapies representing a pioneering breakthrough, SMN protein replacement is not a cure for the disease. In addition, many patients are poor responders for the treatments, highlighting the incomplete understanding of the disease mechanisms. Recent evidence points out that SMA is a systemic and developmental disorder that beyond postnatal spinal MNs malfunction, with many extrinsic influences, such as astrocytes, contributing to MN degeneration.
By single-cell analysis of spinal neuromuscular organoids (SNOs) derived from SMA patients and their isogenic control, we have identified lipid metabolism defects in SMA astrocytes during development. Notably, dysregulation of the critical sterol regulatory element-binding protein, SREBP2, in SMA astrocytes results in deficiencies in cholesterol synthesis, potentially impeding astrocyte maturation and functionality. In addition, SMA astrocytes with cholesterol deficiency impaired neurite outgrowth and reduced resilience of MNs, leading to increased disease susceptibility and severity.
Our proposed research will define a new signaling pathway adding to current SMA disease mechanisms, providing multiple avenues for improving therapeutics and care for SMA patients in the future, and may allow for tailored medicine in the future.
