title: Plastin 3 ameliorates spinal muscular atrophy via delayed axon pruning and improves neuromuscular junction functionality.
abstract: F-actin bundling plastin 3 (PLS3) is a fully protective modifier of the neuromuscular disease spinal muscular atrophy (SMA), the most common genetic cause of infant death. The generation of a conditional PLS3-over-expressing mouse and its breeding into an SMA background allowed us to decipher the exact biological mechanism underlying PLS3-mediated SMA protection. We show that PLS3 is a key regulator that restores main processes depending on actin dynamics in SMA motor neurons (MNs). MN soma size significantly increased and a higher number of afferent proprioceptive inputs were counted in SMAPLS3 compared with SMA mice. PLS3 increased presynaptic F-actin amount, rescued synaptic vesicle and active zones content, restored the organization of readily releasable pool of vesicles and increased the quantal content of the neuromuscular junctions (NMJs). Most remarkably, PLS3 over-expression led to a stabilization of axons which, in turn, resulted in a significant delay of axon pruning, counteracting poor axonal connectivity at SMA NMJs. These findings together with the observation of increased endplate and muscle fiber size upon MN-specific PLS3 over-expression suggest that PLS3 significantly improves neuromuscular transmission. Indeed, ubiquitous over-expression moderately improved survival and motor function in SMA mice. As PLS3 seems to act independently of Smn, PLS3 might be a potential therapeutic target not only in SMA but also in other MN diseases.
authors.affiliation: Institute of Human Genetics, University of Cologne, Kerpener Strasse 34, Cologne, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Ackermann
authors.forename: Sandra
authors.initials: S
authors.lastname: Kröber
authors.forename: Laura
authors.initials: L
authors.lastname: Torres-Benito
authors.forename: Anke
authors.initials: A
authors.lastname: Borgmann
authors.forename: Miriam
authors.initials: M
authors.lastname: Peters
authors.forename: Seyyed Mohsen
authors.initials: SM
authors.lastname: Hosseini Barkooie
authors.forename: Rocio
authors.initials: R
authors.lastname: Tejero
authors.forename: Miriam
authors.initials: M
authors.lastname: Jakubik
authors.forename: Julia
authors.initials: J
authors.lastname: Schreml
authors.forename: Janine
authors.initials: J
authors.lastname: Milbradt
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Wunderlich
authors.forename: Markus
authors.initials: M
authors.lastname: Riessland
authors.forename: Lucia
authors.initials: L
authors.lastname: Tabares
authors.forename: Brunhilde
authors.initials: B
authors.lastname: Wirth
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D019054:Evoked Potentials, Motor; D015870:Gene Expression; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000502:physiology*; D008856:Microscopy, Fluorescence; D009045:Motor Endplate / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D010641:Phenotype; D011434:Proprioception; D021381:Protein Transport; D011950:Receptors, Cholinergic / Q000378:metabolism; D055533:Survival of Motor Neuron 1 Protein / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D013572:Synaptic Vesicles / Q000378:metabolism
chemical_list: D000199:Actins; D008562:Membrane Glycoproteins; D008840:Microfilament Proteins; D011950:Receptors, Cholinergic; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein; C026742:plastin