Acta Neuropathologica

, Volume 115, Issue 3, pp 313–326

Abnormal motoneuron migration, differentiation, and axon outgrowth in spinal muscular atrophy

  • Goran Simic
  • Mihovil Mladinov
  • Durdica Seso Simic
  • Natasa Jovanov Milosevic
  • Atiqul Islam
  • Alen Pajtak
  • Nina Barisic
  • Jadranka Sertic
  • Paul J. Lucassen
  • Patrick R. Hof
  • Bozo Kruslin
Original Paper

DOI: 10.1007/s00401-007-0327-1

Cite this article as:
Simic, G., Mladinov, M., Seso Simic, D. et al. Acta Neuropathol (2008) 115: 313. doi:10.1007/s00401-007-0327-1

Abstract

The role of heterotopic (migratory) motoneurons (HMN) in the pathogenesis of spinal muscular atrophy (SMA) is still controversial. We examined the occurrence and amount of HMN in spinal cord tissue from eight children with SMA (six with SMA-I and two with SMA-II). All affected subjects were carrying a homozygous deletion of exon 7 in the SMN1 gene. Unlike controls, virtually free from HMN, all SMA subjects showed a significant number of HMN at all levels of the spinal cord. Heterotopic neurons were hyperchromatic, located mostly in the ventral white matter and had no axon or dendrites. More than half of the HMN were very undifferentiated, as judged from their lack of immunoreactivity for NeuN and MAP2 proteins. Small numbers of more differentiated heterotopic neurons were also found in the dorsal and lateral white matter region. As confirmed by ultrastructural analysis, in situ end labeling (ISEL) and CD68 immunoreactivity, HMN in the ventral outflow were found to have no synapses, to activate microglial cells, and to eventually die by necrosis. An unbiased quantitative analysis showed a significant negative correlation between age of SMA subjects (a reflection of the clinical severity) and the number of HMN. Subjects who died at older ages had increased number of GFAP-positive astrocytes. Complementing our previous report on motoneuron apoptosis within the ventral horns in SMA, we now propose that abnormal migration, differentiation, and lack of axonal outgrowth may induce motoneuron apoptosis predominantly during early stages, whereas a slower necrosis-like cell death of displaced motoneurons which “escaped” apoptosis characterizes later stages of SMA.

Keywords

MotoneuronsMigrationPathogenesisSpinal muscular atrophySMN1 gene

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Goran Simic
    • 1
  • Mihovil Mladinov
    • 1
  • Durdica Seso Simic
    • 2
  • Natasa Jovanov Milosevic
    • 1
  • Atiqul Islam
    • 3
  • Alen Pajtak
    • 1
  • Nina Barisic
    • 2
  • Jadranka Sertic
    • 2
  • Paul J. Lucassen
    • 4
  • Patrick R. Hof
    • 5
  • Bozo Kruslin
    • 1
  1. 1.Department of Neuroscience, School of Medicine, Croatian Institute for Brain Research, Medical School ZagrebZagreb UniversityZagrebCroatia
  2. 2.University Hospital Center ZagrebZagrebCroatia
  3. 3.Karolinska InstituteStockholmSweden
  4. 4.Centre for Neuroscience, Swammerdam Institute for Life SciencesUniversity of AmsterdamAmsterdamThe Netherlands
  5. 5.Department of NeuroscienceMount Sinai School of MedicineNew YorkUSA