Human molecular genetics

Neuron-specific knock-down of SMN1 causes neuron degeneration and death through an apoptotic mechanism.

PMID 27260405


Spinal muscular atrophy is a devastating disease that is characterized by degeneration and death of a specific subclass of motor neurons in the anterior horn of the spinal cord. Although the gene responsible, survival motor neuron 1 (SMN1), was identified 20 years ago, it has proven difficult to investigate its effects in vivo. Consequently, a number of key questions regarding the molecular and cellular functions of this molecule have remained unanswered. We developed a Caenorhabditis elegans model of smn-1 loss-of-function using a neuron-specific RNA interference strategy to knock-down smn-1 selectively in a subclass of motor neurons. The transgenic animals presented a cell-autonomous, age-dependent degeneration of motor neurons detected as locomotory defects and the disappearance of presynaptic and cytoplasmic fluorescent markers in targeted neurons. This degeneration led to neuronal death as revealed by positive reactivity to genetic and chemical cell-death markers. We show that genes of the classical apoptosis pathway are involved in the smn-1-mediated neuronal death, and that this phenotype can be rescued by the expression of human SMN1, indicating a functional conservation between the two orthologs. Finally, we determined that Plastin3/plst-1 genetically interacts with smn-1 to prevent degeneration, and that treatment with valproic acid is able to rescue the degenerative phenotype. These results provide novel insights into the cellular and molecular mechanisms that lead to the loss of motor neurons when SMN1 function is reduced.