Downregulation of Bcl-2 proteins in type I spinal muscular atrophy motor neurons during fetal development.

Spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by mutations in the survival motor neuron gene. The degeneration and loss of the anterior horn cells constitute the major neuropathological finding in SMA, although the mechanism and timing of this abnormal motor neuron death remain unknown. It has recently been reported that the fetal SMA spinal cord shows a significant increase in cells with DNA fragmentation, suggesting that the programmed cell death is aberrantly increased in type I SMA during development. We have analyzed 2 antiapoptotic proteins, Bcl-2 and Bcl-X, by Western blot and immunohistochemistry screening for differential expression in control and SMA fetal spinal cords. Expression of these proteins was found in various neuronal populations and structures of the developing spinal cord. At 15 weeks, motor neurons of SMA fetuses showed a marked decrease in the levels of Bcl-2 and a delay in the expression of Bcl-X in comparison with controls. The difference in the pattern and degree of expression is consistent with a role for both proteins in the aberrant programmed cell death observed in type I SMA.