Plastin 3 rescues cell surface translocation and activation of TrkB in spinal muscular atrophy

• Published in: The Journal of cell biology 2023-03, Vol.222 (3), p.1
• Main Authors: Hennlein, Luisa, Ghanawi, Hanaa, Gerstner, Florian, Palominos García, Eduardo, Yildirim, Ezgi, Saal-Bauernschubert, Lena, Moradi, Mehri, Deng, Chunchu, Klein, Teresa, Appenzeller, Silke, Sauer, Markus, Briese, Michael, Simon, Christian, Sendtner, Michael, Jablonka, Sibylle
• Format: Article
• Language: English
• Subjects: Actin; Actins - metabolism; Atrophy; Brain-derived neurotrophic factor; Calcium channels (voltage-gated); Carrier Proteins - metabolism; Cell activation; Cell surface; Cytoskeleton; Degeneration; F-actin-binding proteins; Humans; Kinases; Membrane proteins; Membrane Proteins - genetics; Membrane Proteins - metabolism; Microfilament Proteins - genetics; Microfilament Proteins - metabolism; Motor neurons; Motor Neurons - metabolism; Muscular Atrophy, Spinal - genetics; Muscular Atrophy, Spinal - pathology; Mutation; Neurodegeneration; Neuromuscular diseases; Neuroscience; Pediatrics; Presynapse; Proteins; Receptor, trkB - metabolism; SMN protein; Spinal muscular atrophy; Survival of Motor Neuron 1 Protein - metabolism; Terminals; Translocation; TrkB receptors; Tropomyosin
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.202204113

Plastin 3 (PLS3) is an F-actin-bundling protein that has gained attention as a modifier of spinal muscular atrophy (SMA) pathology. SMA is a lethal pediatric neuromuscular disease caused by loss of or mutations in the Survival Motor Neuron 1 (SMN1) gene. Pathophysiological hallmarks are cellular maturation defects of motoneurons prior to degeneration. Despite the observed beneficial modifying effect of PLS3, the mechanism of how it supports F-actin-mediated cellular processes in motoneurons is not yet well understood. Our data reveal disturbed F-actin-dependent translocation of the Tropomyosin receptor kinase B (TrkB) to the cell surface of Smn-deficient motor axon terminals, resulting in reduced TrkB activation by its ligand brain-derived neurotrophic factor (BDNF). Improved actin dynamics by overexpression of hPLS3 restores membrane recruitment and activation of TrkB and enhances spontaneous calcium transients by increasing Cav2.1/2 "cluster-like" formations in SMA axon terminals. Thus, our study provides a novel role for PLS3 in supporting correct alignment of transmembrane proteins, a key mechanism for (moto)-neuronal development.