1. SMN is physiologically down-regulated at wild-type motor nerve terminals but aggregates together with neurofilaments in SMA mouse models
- Author
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Julio Franco-Espin, Alaó Gatius, José Ángel Armengol, Saravanan Arumugam, Mehri Moradi, Michael Sendtner, Jordi Calderó, Lucia Tabares, Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica, Agencia Estatal de Investigación. España, Ministerio de Ciencia e Innovacion, European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER), TV3 Foundation, and Deutsche Forschungsgemeinschaft / German Research Foundation (DFG)
- Subjects
Motor Neurons ,β-actin mRNA ,Beta-actin mRNA ,Intermediate Filaments ,Neuromuscular junction ,SMN Complex Proteins ,Spinal muscular atrophy ,spinal muscular atrophy ,motor neuron degeneration ,SMN granules ,neuromuscular junction ,MAP1B ,neurofilaments ,Ribonucleoproteins, Small Nuclear ,Biochemistry ,Actins ,Muscular Atrophy, Spinal ,Mice ,Disease Models, Animal ,Ribonucleoproteins ,Motor neuron degeneration ,Animals ,RNA, Messenger ,Molecular Biology ,In Situ Hybridization, Fluorescence - Abstract
Survival motor neuron (SMN) is an essential and ubiquitously expressed protein that participates in several aspects of RNA metabolism. SMN deficiency causes a devastating motor neuron disease called spinal muscular atrophy (SMA). SMN forms the core of a protein complex localized at the cytoplasm and nuclear gems and that catalyzes spliceosomal snRNP particle syn-thesis. In cultured motor neurons, SMN is also present in dendrites and axons, and forms part of the ribonucleoprotein transport granules implicated in mRNA trafficking and local translation. Nevertheless, the distribution, regulation, and role of SMN at the axons and presynaptic motor terminals in vivo are still unclear. By using conventional confocal microscopy and STED su-per-resolution nanoscopy, we found that SMN appears in the form of granules distributed along motor axons at nerve terminals. Our fluorescence in situ hybridization and electron microscopy studies also confirmed the presence of β-actin mRNA, ribosomes, and polysomes in the presynap-tic motor terminal, key elements of the protein synthesis machinery involved in local translation in this compartment. SMN granules co-localize with the microtubule-associated protein MAP1B and neurofilaments, suggesting that the cytoskeleton participates in transporting and positioning the granules. We also found that, while SMN granules are physiologically downregulated at the pre-synaptic element during the period of postnatal maturation in wild-type (non-transgenic) mice, they accumulate in areas of neurofilament aggregation in SMA mice, suggesting that the high ex-pression of SMN at the NMJ, together with the cytoskeletal defects, contribute to impairing the bi-directional traffic of proteins and organelles between the axon and the presynaptic terminal. This work was supported by the Spanish Agencia Estatal de Investigación (grant number:PID2019-110272RB-100/AEI/10.13039/501100011033 (LT), SMA Europe (LT), Ministerio de Ciencia eInnovación/FEDER (grant: PID2021-122785OB-I00) (JC)), the Deutsche Forschungsgemeinschaft (Se697/7-1 (MS)), and the Maratóde TV3 Foundation (202005 (JC and LT))
- Published
- 2022
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