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

Abstract

Loss of the survival motor neuron gene (SMN1) is responsible for spinal muscular atrophy (SMA), the most common inherited cause of infant mortality. Even though the SMA phenotype is traditionally considered as related to spinal motor neuron loss, it remains debated whether the specific targeting of motor neurons could represent the best therapeutic option for the disease. We here investigated, using stereological quantification methods, the spinal cord and cerebral motor cortex of ∆7 SMA mice during development, to verify extent and selectivity of motor neuron loss. We found progressive post-natal loss of spinal motor neurons, already at pre-symptomatic stages, and a higher vulnerability of motor neurons innervating proximal and axial muscles. Larger motor neurons decreased in the course of disease, either for selective loss or specific developmental impairment. We also found a selective reduction of layer V pyramidal neurons associated with layer V gliosis in the cerebral motor cortex. Our data indicate that in the ∆7 SMA model SMN loss is critical for the spinal cord, particularly for specific motor neuron pools. Neuronal loss, however, is not selective for lower motor neurons. These data further suggest that SMA pathogenesis is likely more complex than previously anticipated. The better knowledge of SMA models might be instrumental in shaping better therapeutic options for affected patients.

Genome-wide RNA-Seq of Human Motor Neurons Implicates Selective ER Stress Activation in Spinal Muscular Atrophy

“…On average, DMSO-treated SMAΔ7 animals have fewer MNs compared to DMSO-treated wild-type animals (13.5 versus 22.7 ChAT+ MNs per 10 μm section; p = 0.0028), similar to previous reports (d’Errico et al, 2013; Mentis et al, 2011). Importantly, we observed that GUA treatment increased the number of ChAT + MNs by an average of 40 (± 5) % in SMAΔ7 animals compared to DMSO-treated animals ( p = 0.034; Figure 7G), indicating that GUA prevents degeneration of spinal MNs by inhibition of ER stress.…”

“…Previous studies have shown that MN soma sizes are significantly smaller in SMAΔ7 mice as early as PND4 (d’Errico et al, 2013), suggesting that MNs are undergoing atrophy and large MNs are lost even when the animals are pre-symptomatic. We also found that DMSO-treated SMAΔ7 MNs were significantly smaller than DMSO-treated wild-type MNs (220 ± 25 μm 2 in SMA and 316 ± 27 μm 2 in WT; p = 0.0092).…”

Serotonin 2B receptor slows disease progression and prevents degeneration of spinal cord mononuclear phagocytes in amyotrophic lateral sclerosis

“…Only ChAT+ neurons located in a position congruent with that of motoneuron groups were counted [13]. All ChAT + profiles located in the ventral horns of immunostained sections and clearly displayed in the plane of section were counted.…”

ML372 blocks SMN ubiquitination and improves spinal muscular atrophy pathology in mice

“…Similarly, myofiber number was also increased (1,690 to 2,411 myofibers per section) with ML372 treatment ( Figure 4C). Loss of motor neurons is very rapid in the early postnatal stages of this SMA mouse model, with limited motor neuron loss after PND7 (24,25). Nissl staining of lumbar spinal cord segments ( Figure 4D) showed that ML372 increased motor neuron size ( Figure 4E, mean somatic diameter of 37.2 μm compared with 32.9 μm in vehicle-treated animals), with no change in the number of motor neurons ( Figure 4F).…”