Abstract
Spinal muscular atrophy (SMA) is a hereditary childhood disease that causes paralysis and progressive degeneration of skeletal muscles and spinal motor neurons. SMA is associated with reduced levels of full-length Survival of Motor Neuron (SMN) protein, due to mutations in the Survival of Motor Neuron 1 gene. Nowadays there are no effective therapies available to treat patients with SMA, so our aim was to test whether the non-toxic carboxy-terminal fragment of tetanus toxin heavy chain (TTC), which exhibits neurotrophic properties, might have a therapeutic role or benefit in SMA. In this manuscript, we have demonstrated that TTC enhance the SMN expression in motor neurons “in vitro” and evaluated the effect of intramuscular injection of TTC-encoding plasmid in the spinal cord and the skeletal muscle of SMNdelta7 mice. For this purpose, we studied the weight and the survival time, as well as, the survival and cell death pathways and muscular atrophy. Our results showed that TTC treatment reduced the expression of autophagy markers (Becn1, Atg5, Lc3, and p62) and pro-apoptotic genes such as Bax and Casp3 in spinal cord. In skeletal muscle, TTC was able to downregulate the expression of the main marker of autophagy, Lc3, to wild-type levels and the expression of the apoptosis effector protein, Casp3. Regarding the genes related to muscular atrophy (Ankrd1, Calm1, Col19a1, Fbox32, Mt2, Myod1, NogoA, Pax7, Rrad, and Sln), TTC suggest a compensatory effect for muscle damage response, diminished oxidative stress and modulated calcium homeostasis. These preliminary findings suggest the need for further experiments to depth study the effect of TTC in SMA disease.
Highlights
Motor neuron diseases, a group of heterogeneous neurological disorders such as Amyotrophic Lateral Sclerosis (ALS) and Spinal Muscular Atrophy (SMA), are characterized by varying degrees of motor neuron degeneration
The results obtained showed that, 10 days after inoculation, tetanus toxin heavy chain (TTC) treatment significantly increased the levels of the Survival of Motor Neuron (SMN) gene in muscle and spinal cord tissues in this animal model
Calm1 in wild type (WT) mice (WT, black bars), untreated SMA mice (SMA-C, dark gray bars) and SMA mice treated with TTC (SMA-TTC, light gray bars) in skeletal muscle tissue
Summary
A group of heterogeneous neurological disorders such as Amyotrophic Lateral Sclerosis (ALS) and Spinal Muscular Atrophy (SMA), are characterized by varying degrees of motor neuron degeneration. SMA is an autosomal recessive motor neuron disease and the first genetic cause of infant mortality, characterized by the degeneration of motor neurons in the anterior horn of the spinal cord, resulting in muscular atrophy and weakness. SMA patients have a homozygous loss of the survival motor neuron 1 (SMN1) gene, but retain one or more copies of a nearly identical homolog, SMN2. This disease is the result of insufficient amounts of SMN protein and its levels are generally inversely correlated with the severity of the disease, making SMN2 copy number the predominant modifier of the neuromuscular phenotype (Monani and De Vivo, 2014). The most interesting therapeutic strategies are represented by molecular, gene and stem cell-mediated approaches which are focused on activating SMN2 expression, modulating splicing of SMN2 or replacing SMN1 (Zanetta et al, 2014; d’Ydewalle and Sumner, 2015)
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