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Spinal muscular atrophy (SMA) is a severe neurodegenerative disorder that occurs in early childhood. The disease is caused by the deletion/mutation of the survival motor neuron 1 (SMN1) gene resulting in progressive skeletal muscle atrophy and paralysis, due to the degeneration of spinal motor neurons (MNs). Currently, the cellular and molecular mechanisms underlying MN death are only partly known, although recently it has been shown that the c-Jun NH 2 -terminal kinase (JNK)-signaling pathway might be involved in the SMA pathogenesis. After confirming the activation of JNK in our SMA mouse model (SMN2+/+; SMNΔ7+/+; Smn-/-), we tested a specific JNK-inhibitor peptide (D-JNKI1) on these mice, by chronic administration from postnatal day 1 to 10, and histologically analyzed the spinal cord and quadriceps muscle at age P12. We observed that D-JNKI1 administration delayed MN death and decreased inflammation in spinal cord. Moreover, the inhibition of JNK pathway improved the trophism of SMA muscular fibers and the size of the neuromuscular junctions (NMJs), leading to an ameliorated innervation of the muscles that resulted in improved motor performances and hind-limb muscular tone. Finally, D-JNKI1 treatment slightly, but significantly increased lifespan in SMA mice. Thus, our results identify JNK as a promising target to reduce MN cell death and progressive skeletal muscle atrophy, providing insight into the role of JNK-pathway for developing alternative pharmacological strategies for the treatment of SMA.

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.

We have studied the development of NADPH-diaphorase activity in the retinorecipient layers of the superior colliculus (SC) in rats from embryonic day 17 to adulthood, during aging, and following neonatal tetrodotoxin injection or unilateral eye removal in the neonatal or in the adult animal. In the superficial SC, NADPH-d activity is first seen in neurons on postnatal day (P) 4; over the next two weeks, enzyme expression increases gradually, in cells as well as in the neuropil. By P12-14, around the time of eye opening, NADPH-d reactivity increases dramatically. In parallel, the dendrites of many NADPH-d-positive neurons in the superficial gray layer, more or less randomly distributed at first, gradually align their orientation relative to the dorsoventral axis. The pattern of NADPH-d activity in the superficial layers of the SC (i.e. stratum griseum superficiale and stratum opticum) is adult-like by the fourth week of age. Deafferentation of the superficial SC, both in the neonatal and adult rat, and block of retinal activity lead to reduction in the size of the SC and changes in NADPH-d-positive neurons, including dendrite misorientation, decreased cell size and reduced number. Some of these changes are seen also in the aging animal. These results document a protracted and progressive increase in the development of NADPH-d expression in the SC. Our results suggest a strong influence of retinal afferents and activity on the development and maintenance of NAPHD-positive neurons in the retinorecipient layers of the SC, where NO can act as a retrograde signal to carve the terminal arbors of retinal axons.