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

Abstract

Abnormal motoneuron migration, differentiation, and axon outgrowth in spinal muscular atrophy. Acta Neuropathologica, 115 (3). pp. 313-326. 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 SMAII). 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.

Selective Vulnerability of Spinal and Cortical Motor Neuron Subpopulations in delta7 SMA Mice

“…In this respect, intramuscular administration of adenoviral vectors expressing cardiotrophin-1 improved motor performance and increased survival in a SMA model [59], indicating that cytokines might modulate the neurodegenerative process in SMA. The present data are in agreement with the report of gliosis in the spinal cord of SMAI and SMAII patients [47], and support the idea that also neuroinflammation should be considered as a potential therapeutic target for tackling SMA.…”

“…Apoptotic mechanisms can also play a major role in motor neuron death in SMA, as suggested by data from human post-mortem specimens of SMA type I patients [43,44] and animal models [45,46]. Finally, it should be remembered that failure in motor neuron migration was proposed as the key step to understand motor neuron loss and hence pathogenesis in human SMA [47]. …”

Spinal Muscular Atrophy and a Model for Survival of Motor Neuron Protein Function in Axonal Ribonucleoprotein Complexes

“…Likewise, we need to compare observations in human patients with the findings in model organisms. For example, in a recent study, SMA-I and SMA-II spinal cords showed a significant number of motor neurons that had migrated aberrantly toward the ventral spinal roots (Simic 2008; Simic et al 2008). These heterotopic motor neurons (HMN) were located mostly in the ventral white matter and had no axon or dendrites.…”

Survival of motor neuron protein over-expression prevents calpain-mediated cleavage and activation of procaspase-3 in differentiated human SH-SY5Y cells

“…In SMA, a significant number of motor neurons in the spinal cord die by a process characteristic of apoptosis (Simic et al, 2000;Tsai et al, 2006;Simic et al, 2008).…”