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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 \u201ccluster-like\u201d 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.<\/jats:p>","DOI":"10.1083\/jcb.202204113","type":"journal-article","created":{"date-parts":[[2023,1,6]],"date-time":"2023-01-06T14:15:46Z","timestamp":1673014546000},"update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":23,"title":["Plastin 3 rescues cell surface translocation and activation of TrkB in spinal muscular atrophy"],"prefix":"10.1083","volume":"222","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4962-8259","authenticated-orcid":true,"given":"Luisa","family":"Hennlein","sequence":"first","affiliation":[{"name":"Institute of Clinical Neurobiology, University Hospital W\u00fcrzburg 1 , W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1928-6139","authenticated-orcid":true,"given":"Hanaa","family":"Ghanawi","sequence":"additional","affiliation":[{"name":"Institute of Clinical Neurobiology, University Hospital W\u00fcrzburg 1 , W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6529-1660","authenticated-orcid":true,"given":"Florian","family":"Gerstner","sequence":"additional","affiliation":[{"name":"Carl-Ludwig-Institute for Physiology, Leipzig University 2 , Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7639-3811","authenticated-orcid":true,"given":"Eduardo","family":"Palominos Garc\u00eda","sequence":"additional","affiliation":[{"name":"Institute of Clinical Neurobiology, University Hospital W\u00fcrzburg 1 , W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9242-6273","authenticated-orcid":true,"given":"Ezgi","family":"Yildirim","sequence":"additional","affiliation":[{"name":"Institute of Clinical Neurobiology, University Hospital W\u00fcrzburg 1 , W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7396-2057","authenticated-orcid":true,"given":"Lena","family":"Saal-Bauernschubert","sequence":"additional","affiliation":[{"name":"Institute of Clinical Neurobiology, University Hospital W\u00fcrzburg 1 , W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9550-8701","authenticated-orcid":true,"given":"Mehri","family":"Moradi","sequence":"additional","affiliation":[{"name":"Institute of Clinical Neurobiology, University Hospital W\u00fcrzburg 1 , W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5533-6009","authenticated-orcid":true,"given":"Chunchu","family":"Deng","sequence":"additional","affiliation":[{"name":"Institute of Clinical Neurobiology, University Hospital W\u00fcrzburg 1 , W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1155-0361","authenticated-orcid":true,"given":"Teresa","family":"Klein","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Biophysics, Biocenter, Julius-Maximilians-University W\u00fcrzburg 3 , W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5472-8692","authenticated-orcid":true,"given":"Silke","family":"Appenzeller","sequence":"additional","affiliation":[{"name":"Comprehensive Cancer Center Mainfranken; 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