Published online before print August 23, 2007

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(American Journal of Pathology. 2007;171:1269-1280.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.070399

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

Jérémie Vitte^*, Coralie Fassier^*, Francesco D. Tiziano, Cécile Dalard^*, Sabrina Soave^*, Natacha Roblot^*, Christine Brahe, Pascale Saugier-Veber, Jean Paul Bonnefont and Judith Melki^*

From the Molecular Neurogenetics Laboratory,^* INSERM U798, Evry and Paris 11 Universities, Evry, France; the Department of Genetics, Rouen University Hospital and INSERM U614, Institute for Biochemical Research, University of Rouen, Rouen, France; Hôpital Necker-Enfants Malades, INSERM, U393, Paris, France; and the Institute of Medical Genetics, Catholic University, Rome, Italy

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 (SMN⁷), the major product of the SMN2 gene, had a dominant-negative effect. We generated antibodies specific to SMN^FL or SMN⁷. In transfected cells, the stability of the SMN⁷ protein was regulated in a cell-dependent manner. Importantly, whatever the human tissues examined, SMN⁷ protein was undetectable because of the instability of the protein, thus excluding a dominant effect of SMN⁷ in SMA. A similar decreased level of SMN^FL was observed in brain and spinal cord samples from human SMA, suggesting that SMN^FL 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 SMN^FL in spinal cord when compared with brain tissue. Improving the stability of SMN⁷ protein might be envisaged as a new therapeutic strategy in SMA.

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