Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease, representing the most common inherited cause of infant mortality. Loss of the survival motor neuron gene (SMN1) leads to motor impairment, weakness, atrophy, and premature death caused by motor neuron degeneration. Even though SMA etiology is known and is traditionally considered as related to spinal motor neuron loss, discrepancies still exist on number/subgroups of lower motor neurons affected during disease progression. Furthermore, analysis of brain morphology and evaluation of a possible vulnerability of the upper motor system have not been carried out in the murine model. In order to clarify such alterations, we employed the murine model delta7 SMA (representing the intermediate form of SMA), with a lifespan of about 2 weeks and early motor behavior impairment correlated with motor neuron loss. We collected brains and spinal cords from delta7 SMA and WT mice at embryonic day 19, postnatal day 4 (P4) and P13 for neuron counts and immunohistochemisty. Using stereological quantification methods, we investigated the cervical spinal cord and cerebral motor cortex of 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. We also observed a selective reduction of layer V pyramidal neurons associated with layer V gliosis in the cerebral motor cortex. Our data indicate that in the delta7 SMA model SMN loss is critical for the spinal cord, particularly for specific motor neuron pools. Additionally, neuronal loss is not selective for lower motor neurons. These data further suggest that SMA pathogenesis is likely more complex than previously anticipated. Understanding properly the nature and progression of the anatomopathological manifestations of the disease can give useful suggestions for more efficient therapeutic interventions.
SELECTIVE VULNERABILITY OF SPINAL AND CORTICAL MOTOR NEURON SUBPOPULATIONS IN DELTA7 SMA MICE.
BOIDO, Marina Maria;PIRAS, ANTONIO;VALSECCHI, Valeria;VERCELLI, Alessandro
2014-01-01
Abstract
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease, representing the most common inherited cause of infant mortality. Loss of the survival motor neuron gene (SMN1) leads to motor impairment, weakness, atrophy, and premature death caused by motor neuron degeneration. Even though SMA etiology is known and is traditionally considered as related to spinal motor neuron loss, discrepancies still exist on number/subgroups of lower motor neurons affected during disease progression. Furthermore, analysis of brain morphology and evaluation of a possible vulnerability of the upper motor system have not been carried out in the murine model. In order to clarify such alterations, we employed the murine model delta7 SMA (representing the intermediate form of SMA), with a lifespan of about 2 weeks and early motor behavior impairment correlated with motor neuron loss. We collected brains and spinal cords from delta7 SMA and WT mice at embryonic day 19, postnatal day 4 (P4) and P13 for neuron counts and immunohistochemisty. Using stereological quantification methods, we investigated the cervical spinal cord and cerebral motor cortex of 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. We also observed a selective reduction of layer V pyramidal neurons associated with layer V gliosis in the cerebral motor cortex. Our data indicate that in the delta7 SMA model SMN loss is critical for the spinal cord, particularly for specific motor neuron pools. Additionally, neuronal loss is not selective for lower motor neurons. These data further suggest that SMA pathogenesis is likely more complex than previously anticipated. Understanding properly the nature and progression of the anatomopathological manifestations of the disease can give useful suggestions for more efficient therapeutic interventions.
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