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

Abstract

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.

• Authors: 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
• Journal: The Journal of cell biology (J Cell Biol) Vol. 222 Issue 3 (03 06 2023) ISSN: 1540-8140 [Electronic] United States
• PMID: 36607273 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023 Hennlein et al.

Chemical References

• Actins
• Carrier Proteins
• Microfilament Proteins
• plastin
• Survival of Motor Neuron 1 Protein
• Membrane Proteins
• tropomyosin-related kinase-B, human
• Receptor, trkB

Topics

• Humans
• Actins (metabolism)
• Carrier Proteins (metabolism)
• Microfilament Proteins (genetics, metabolism)
• Motor Neurons (metabolism)
• Muscular Atrophy, Spinal (genetics, pathology)
• Survival of Motor Neuron 1 Protein (metabolism)
• Membrane Proteins (genetics, metabolism)
• Receptor, trkB (metabolism)