Plastin 3 rescues deficient TrkB/BDNF signaling and protects from dysregulations in Ca2+ homeostasis in SMA mouse models

Spinal muscular atrophy (SMA) is a lethal pediatric neuromuscular disease caused by loss of the Survival Motor Neuron 1 gene (SMN1). Although current therapies focus very efficiently on SMN restoration, the cellular mechanisms underlying the pathological features are not fully understood. Smn-deficient motoneurons tremendously suffer from functional abnormalities leading to affected motoneuron differentiation and maturation. Based on our study, we could illustrate disturbed F-actin-dependent translocation of the Tropomyosin-kinase receptor B (TrkB) to the cell surface of axonal terminals of Smn-deficient motoneurons. This in turn results in impaired Brain-derived neurotrophic factor-induced TrkB activation and downstream signaling. Focusing on the F-actin bundling properties of the protective SMA modifier Plastin 3 revealed that its restoration significantly compensates altered TrkB surface recruitment and activation and ameliorates Cav2.1/2 cluster formation and cellular excitability in Smn-deficient motor axons. Thus, Plastin 3 supports in general two major cellular mechanisms indispensable for development and functional maintenance of motoneurons. Overall design: Total number of samples is 12