Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by a progressive loss of the spinal motoneurons. The SMA-determining gene has been termed survival motor neuron (SMN) and is deleted or mutated in over 98% of patients. The encoded gene product is a protein expressed as different isoforms. In particular, we showed that the rat SMN cDNA produces two isoforms with Mr of 32 and 35 kDa, both localized in nuclear coiled bodies, but the 32 kDa form is also cytoplasmic, whereas the 35 kDa form is also microsomal. To determine the molecular relationship between these two isoforms and potential post-translational modifications, we performed transfection experiments with a double-tagged rat SMN. Immunoblot and immunostaining studies demonstrated that the 32 kDa SMN isoform derives from the full length 35 kDa, through a proteolytic cleavage at the C-terminal. Furthermore, the 35 kDa SMN isoform is physiologically phosphorylated in vivo. This may modulate its interaction with molecular partners, either proteins or nucleic acids. (C) 2004 Elsevier Inc. All rights reserved.