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.
Plastin 3 rescues cell surface translocation and activation of TrkB in spinal muscular atrophy
Disclosures: The authors declare no competing interests exist.
H. Ghanawi’s current affiliation is Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-Universität München, München, Germany.
L. Saal-Bauernschubert’s current affiliation is Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, University Hospital Würzburg, Würzburg, Germany.
- Award Id(s): JA 1823/3-1,SE 697/6-1,SI 1969/2-1,SI 1969/3-1,BR 4910/2–1
- Award Id(s): JAB1920
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Luisa Hennlein, Hanaa Ghanawi, Florian Gerstner, Eduardo Palominos García, Ezgi Yildirim, Lena Saal-Bauernschubert, Mehri Moradi, Chunchu Deng, Teresa Klein, Silke Appenzeller, Markus Sauer, Michael Briese, Christian Simon, Michael Sendtner, Sibylle Jablonka; Plastin 3 rescues cell surface translocation and activation of TrkB in spinal muscular atrophy. J Cell Biol 6 March 2023; 222 (3): e202204113. doi: https://doi.org/10.1083/jcb.202204113
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