Abstract Spinal muscular atrophy (SMA) is a paediatric neuromuscular disease caused by alterations of the survival motor neuron ( SMN ) gene, which results in progressive degeneration of motor neurons (MNs). Although effective treatments for SMA patients has been recently developed, the molecular pathway involved in selective MNs degeneration has not been yet elucidated. Disruption of axonal transport is a common feature of motor neuron diseases (MNDs); specifically, mutations at the C-terminal of the kinesin KIF5A, have been linked to neurodegenerative disorders involving MNs degeneration such as amyotrophic lateral sclerosis (ALS). Therefore, the present study attempts to investigate potential alterations of the axonal transport complex that includes KIF5A in a SMA mouse model. We demonstrated that KIF5A is downregulated in the spinal cord of SMA mice both in early and late phases of the disease. A miRNA-based strategy was developed in the attempt to prevent KIF5A downregulation, thus restoring its physiological levels. Indeed, we demonstrated that miR-140-3p was up-regulated in the spinal cord of SMA mice during disease progression and was able to negatively modulate KIF5A expression. Furthermore, the intracerebroventricular injection of an antagomir molecule, able to block miR140-3p function, resulted in a reduction of SMA severity in terms of improved behavioural performance. Based on these results, we indicated KIF5A as a distinctive mechanism of MNDs progression and suggested that developing a strategy able to prevent KIF5A downregulation could be beneficial, not only in SMA but also in other neurodegenerative diseases.
Baklou et al. (Tue,) studied this question.