Pharmacological c-Jun NH2-Terminal Kinase (JNK) Pathway Inhibition Reduces Severity of Spinal Muscular Atrophy Disease in Mice.

Roberta Schellino,Tiziana Borsello,Marina Boido,Alessandro Vercelli

doi:10.3389/fnmol.2018.00308

Abstract

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 NH2-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.

Highlights

Spinal Muscular Atrophy (SMA) is a recessive autosomal neuromuscular disease that represents the most common fatal pathology in infancy
Here we investigated the possibility to impact on Spinal muscular atrophy (SMA) progression by Jun NH2-terminal kinase (JNK) inhibition: to this aim, we administered to SMN∆7 mice a cell-penetrating JNK inhibitor (D-JNKI1) peptide, which selectively blocks the access of JNK to c-Jun and the other JNK-binding domain (JBD) dependent targets
To shed light on the cell death type ongoing in SMA and understand the potential role of JNK pathway in the disease pathogenesis, by WB analysis we first quantified the p-c-Jun protein fraction in spinal cords of P12 SMA and WT pups: we found an increase of about 20% in relative phosphorylation intensity in SMA group compared to WT (p = 0.014, Figure 1A), confirming the results of Genabai et al.’s (2015) group

Summary

Introduction

Spinal Muscular Atrophy (SMA) is a recessive autosomal neuromuscular disease that represents the most common fatal pathology in infancy. The disease is caused by the mutation or deletion of the survival motor neuron 1 (SMN1) gene, that leads to a progressive degeneration of spinal motor neurons (MNs), resulting in the atrophy of the muscles of the limbs and trunk, and lastly in death for respiratory complications (Lorson et al, 1999). Investigating the molecular and cellular mechanisms of cell death leading to MN degeneration could be extremely relevant to prevent and/or delay the disease progression. In the last years different translational approaches, both SMN-dependent (e.g., RNA-based modulation of SMN2) and SMN-independent (e.g., neurotrophic factors, stem cells), have been adopted to develop therapeutics for SMA patients (Lorson et al, 2010; Boido and Vercelli, 2016), the molecular pathways involved in neurodegeneration remain unknown

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