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The c-Jun N-terminal kinase (JNK) is part of a stress signalling pathway strongly activated by NMDA-stimulation and involved in synaptic plasticity. Many studies have been focused on the post-synaptic mechanism of JNK action, and less is known about JNK presynaptic localization and its physiological role at this site. Here we examined whether JNK is present at the presynaptic site and its activity after presynaptic NMDA receptors stimulation. By using N-SIM Structured Super Resolution Microscopy as well as biochemical approaches, we demonstrated that presynaptic fractions contained significant amount of JNK protein and its activated form. By means of modelling design, we found that JNK, via the JBD domain, acts as a physiological effector on T-SNARE proteins; then using biochemical approaches we demonstrated the interaction between Syntaxin-1-JNK, Syntaxin-2-JNK, and Snap25-JNK. In addition, taking advance of the specific JNK inhibitor peptide, D-JNKI1, we defined JNK action on the SNARE complex formation. Finally, electrophysiological recordings confirmed the role of JNK in the presynaptic modulation of vesicle release. These data suggest that JNK-dependent phosphorylation of T-SNARE proteins may have an important functional role in synaptic plasticity., Competing Interests: There is no actual or potential conflict of interests.

Spinal muscular atrophy (SMA) is a recessive autosomal neuromuscular disease, characterized by motor impairment, muscle atrophy and premature death following motor neuron (MN) degeneration, due to the lack of SMN (survival motor neuron) protein. Currently, the cellular and molecular mechanisms underlying MN death are only partly known [1], although recently it has been shown that the JNK-signalling pathway might be involved in the SMA pathogenesis. After confirming the activation of JNK in our SMA mouse model (SMN2+/+; SMNδ7+/+; Smn-/-), we tested on these mice a synthetic JNK-inhibitor peptide (D-JNKI), by chronic administration from postnatal day 1 (P1) to P10; then, at age P12, we analyzed their spinal cords and quadriceps muscles. We observed that D-JNKI administration delayed MN death and decreased neuroinflammation in the spinal cord. Moreover, by inhibiting JNK pathway, the muscular fibers and the neuromuscular junctions appeared respectively more trophic and mature. The histological/molecular results positively correlated with improved motor performances and hindlimb muscular tone. Finally, the treatment slightly, but significantly increased lifespan in SMA mice. Overall, 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.This work was supported by grants from CRT Foundation, Girotondo/ONLUS and SMArathon-ONLUS foundations. [ABSTRACT FROM AUTHOR]