Refined Characterization of the Expression and Stability of the SMN Gene Products

Spinal muscular atrophy (SMA) is characterized by degeneration of lower motor neurons and caused by mutations of the SMN1 gene. SMN1 is duplicated in a homologous gene called SMN2 , which remains present in patients. SMN has an essential role in RNA metabolism, but its role in SMA pathogenesis remains unknown. Previous studies suggested that in neurons the protein lacking the C terminus (SMNΔ7 ), the major product of the SMN2 gene, had a dominant-negative effect. We generated antibodies specific to SMNFL or SMNΔ7 . In transfected cells, the stability of the SMNΔ7 protein was regulated in a cell-dependent manner. Importantly, whatever the human tissues examined, SMNΔ7 protein was undetectable because of the instability of the protein, thus excluding a dominant effect of SMNΔ7 in SMA. A similar decreased level of SMNFL was observed in brain and spinal cord samples from human SMA, suggesting that SMNFL may have specific targets in motor neurons. Moreover, these data indicate that the vulnerability of motor neurons cannot simply be ascribed to the differential expression or a more dramatic reduction of SMNFL in spinal cord when compared with brain tissue. Improving the stability of SMNΔ7 protein might be envisaged as a new therapeutic strategy in SMA.