Associate Professor The University of Hong Kong The University of Hong Kong, United States
Abstract: Spinal muscular atrophy (SMA) is a genetic neuromuscular disease caused by the loss of the ubiquitously expressed survival motor neuron 1 (SMN1) protein, resulting in progressive degeneration of spinal motor neurons and muscular atrophy. The selective impact of global SMN deficiency on motor neuron integrity remains elusive. Here, we show that the Rho GTPase-activating protein DLC1 isoform 1 (DLC1-i1) is expressed in human MNs and crucial for axon outgrowth and survival. Reduced DLC1-i1 expression contributes to impaired neuromuscular junction (NMJ) formation and increased cell death in neuromuscular organoids differentiated from SMA patients’ urine-derived induced pluripotent stem cells. Conversely, overexpression of DLC1-i1 reverse these phenotypes by enhancing motor axon regeneration. Furthermore, DLC1-i1 expression is significantly reduced in the lumbar spinal cord of SMA mice, and postnatal knockout of Dlc1 in the neuronal cells recapitulates the neuromuscular defects observed in SMA mice. Gene therapy with DLC1-i1 proved more effective than SMN1 in extending lifespan and improving locomotor function in SMA mice, which can be enhanced by co-administration of DLC1-i1+SMN1. Mechanistically, DLC1-i1 not only enhances SMN2 exon 7 inclusion and SMN protein levels by binding with hnRNPC to both exon and intron 7, but also promotes motor axon outgrowth by interacting with mRNAs encoding mitochondria ATP production. In summary, our findings reveal that deficiency of motor neuron-specific DLC1-i1 is a key contributor of NMJ defects in SMA, and restoration of DLC1-i1 expression represents a more effective therapeutic approach for SMA.
Funding Source: Research Grants Council and University Council of Hong Kong (GRF_17114619 , GRF_17114817) Li Po Shan/Dr Vincent Lui Endowment Fund for Motor Neurone Disease Research Impact Fund (R7018-23F)
