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The origin and role of heterotopic motoneurons in the pathogenesis of spinal muscular atrophy

The origin and role of heterotopic (displaced or migratory) motoneurons (HMN) in the pathogenesis of spinal muscular atrophy (SMA) have been a matter of debate for many decades. We have shown that, unlike controls, SMA patients with confirmed homozygous deletion of exon 7 in the SMN1 gene display a significant number of HMN at all levels of the spinal cord (Acta Neuropathol. 2008). HMN are located in the ventral white matter and anterior roots, have no axon or dendrites, and appear hyperchromatic in Nissl-stained sections. Their number positively correlates with clinical severity. Based on our data, we propose that four “ types” of anterior horns neurons exist in the spinal cord of SMA subjects: 1. Morphologically normal motoneurons in their normal position - usually the smallest population of anterior horns neurons seen ; 2. Morphologically abnormal motoneurons in their normal position, i.e., chromatolytic neurons with compromized axon which die slowly by necrotic cell death ; 3. Apoptotic motoneurons in the ventral horns. Although the number of these neurons is relatively low (on average 2-3% of the remaining anterior horns neurons), as they die very rapidly and disappear due to heterophagic elimination by activated microglial cells, their cumulative number is probably largely underestimated. We believe that these neurons may have migrate abnormally, but die due to activation of apoptosis before leaving the spinal gray ; 4. Truly heterotopic (migratory) motoneurons which somehow “ escaped” apoptosis, migrated along the ventral outflow and accumulated at the anterior rim or ventral roots of the spinal cord. We found HMN to have no synapses, to activate microglial cells, and to die eventually by necrosis. In conclusion, we demonstrated that abnormal migration, differentiation, and axon outgrowth of anterior horns neurons may represent the major pathogenetic mechanism of SMA. How exactly SMA mutations prevent axono- and dendrogenesis of anterior horns neurons and cause their aberrant migration remains to be elucidated. Because most of the HMN cells do not express for markers of mature, differentiated neurons (such as NeuN and MAP2 proteins), this raises the possibility that some of them may actually represent adult stem cells. To answer this question, we currently analyze expression of nestin (which is expressed predominantly in neural stem cells and not in mature cells of the central nervous system) and developmental markers of motor neurons (such as islet, lim, and HB9).

migration; motoneurons; pathogenesis; spinal muscular atrophy; SMN1 gene

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