Original Paper

Acta Neuropathologica

, Volume 115, Issue 3, pp 313-326

First online:

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

  • Goran SimicAffiliated withDepartment of Neuroscience, School of Medicine, Croatian Institute for Brain Research, Medical School Zagreb, Zagreb University Email author 
  • , Mihovil MladinovAffiliated withDepartment of Neuroscience, School of Medicine, Croatian Institute for Brain Research, Medical School Zagreb, Zagreb University
  • , Durdica Seso SimicAffiliated withUniversity Hospital Center Zagreb
  • , Natasa Jovanov MilosevicAffiliated withDepartment of Neuroscience, School of Medicine, Croatian Institute for Brain Research, Medical School Zagreb, Zagreb University
  • , Atiqul IslamAffiliated withKarolinska Institute
  • , Alen PajtakAffiliated withDepartment of Neuroscience, School of Medicine, Croatian Institute for Brain Research, Medical School Zagreb, Zagreb University
  • , Nina BarisicAffiliated withUniversity Hospital Center Zagreb
  • , Jadranka SerticAffiliated withUniversity Hospital Center Zagreb
  • , Paul J. LucassenAffiliated withCentre for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam
    • , Patrick R. HofAffiliated withDepartment of Neuroscience, Mount Sinai School of Medicine
    • , Bozo KruslinAffiliated withDepartment of Neuroscience, School of Medicine, Croatian Institute for Brain Research, Medical School Zagreb, Zagreb University

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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

Motoneurons Migration Pathogenesis Spinal muscular atrophy SMN1 gene