Repozitorij Medicinskog fakulteta Sveučilišta u Zagrebu

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

Šimić, Goran and Mladinov, Mihovil and Šešo Šimić, Đurđica and Jovanov Milošević, Nataša and Islam, Atiqul and Pajtak, Alen and Barišić, Nina and Sertić, Jadranka and Lucassen, Paul J. and Hof, Patrick R. and Krušlin, Božo (2008) Abnormal motoneuron migration, differentiation, and axon outgrowth in spinal muscular atrophy. Acta Neuropathologica, 115 (3). pp. 313-326. ISSN 0001-6322 (Print) 1432-0533 (Electronic)

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    English 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.

    Item Type: Article
    MeSH: Axons - metabolism - pathology ; Cell Differentiation - physiology ; Cell Movement - physiology ; Motor Neurons - metabolism - pathology ; Spinal Muscular Atrophies of Childhood - metabolism - pathology ; Brain - metabolism - pathology ; Humans ; Immunohistochemistry ; In Situ Nick-End Labeling ; Muscle, Skeletal - metabolism - pathology ; Spinal Cord - metabolism - pathology
    Divisions: Katedra za pedijatriju
    Katedra za medicinsku kemiju, biokemiju i kliničku kemiju
    Hrvatski institut za istraživanje mozga
    Katedra za patologiju
    Depositing User: Lea Škorić
    Status: Published
    Šimić, Goran
    Mladinov, Mihovil
    Šešo Šimić, Đurđica
    Jovanov Milošević, Nataša
    Islam, Atiqul
    Pajtak, Alen
    Barišić, Nina
    Sertić, Jadranka
    Lucassen, Paul J.
    Hof, Patrick R.
    Krušlin, Božo
    Date: March 2008
    Date Deposited: 25 Feb 2008
    Last Modified: 23 Sep 2011 18:10
    Subjects: /
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