engleski

Abnormal motoneuron migration in spinal muscular atrophy

Together with the "empty cell beds", migratory motoneurons are one of the hallmark neuropathological findings in spinal muscular atrophy (SMA). However, the importance of this phenomenon in the pathogenesis of SMA has been largely underestimated in both classical and contemporary studies. We re-examined the occurrence of migrating motoneurons in spinal cords of 8 children with clinically, pathologically, and genetically confirmed SMA (6 SMA-I and 2 SMA-II). Genotyping was performed using PCR by amplifying exons 7 and 8 of the SMN, and exon 5 of the NAIP gene. All of the patients had documented mutations of SMN exon 7, SMN exon 8, or both. Following fixation in formaldehyde in PBS, each spinal cord was serially cut in the rostrocaudal direction in 25 microns thick sections and stained with cresyl-violet. Out of 3, 307 serial sections analyzed, 210 sections contained migratory motoneurons. In these 210 sections, 597 migratory motoneurons we found. Most of the migratory motoneurons were located in the white matter of the anterior part of the spinal cord while sometimes, they went as far as into the anterior spinal root. In comparison with the motoneurons that remained in the gray matter of the anterior horns which were usually chromatolytic, the migratory motoneurons were never chromatolytic, but hyperchromatic and, in contrast to some published schematic drawings, oval-shaped (undifferentiated). Previously, we were the first to demonstrate apoptotic motoneuron death in SMA-I (Simic et al., JNEN 2000). Since apoptotic neurons could be found only inside the gray matter of the anterior horns, we concluded that abnormally migrating motoneurons escaped apoptosis. This novel finding of such a huge number of migratory motoneurons also suggests that the defect in cell contacts or synaptogenesis may be the predominant pathogenetic mechanism of SMA. How mutations in the SMA-determining SMN gene cause abnormal migration remains to be elucidated.

spinal muscular atrophy; migration; motoneurons; SMN gene; SMN protein; cell death

nije evidentirano