title: Proteomic Analysis of Dynein-Interacting Proteins in Amyotrophic Lateral Sclerosis Synaptosomes Reveals Alterations in the RNA-Binding Protein Staufen1.
abstract: Synapse disruption takes place in many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, the mechanistic understanding of this process is still limited. We set out to study a possible role for dynein in synapse integrity. Cytoplasmic dynein is a multisubunit intracellular molecule responsible for diverse cellular functions, including long-distance transport of vesicles, organelles, and signaling factors toward the cell center. A less well-characterized role dynein may play is the spatial clustering and anchoring of various factors including mRNAs in distinct cellular domains such as the neuronal synapse. Here, in order to gain insight into dynein functions in synapse integrity and disruption, we performed a screen for novel dynein interactors at the synapse. Dynein immunoprecipitation from synaptic fractions of the ALS model mSOD1(G93A) and wild-type controls, followed by mass spectrometry analysis on synaptic fractions of the ALS model mSOD1(G93A) and wild-type controls, was performed. Using advanced network analysis, we identified Staufen1, an RNA-binding protein required for the transport and localization of neuronal RNAs, as a major mediator of dynein interactions via its interaction with protein phosphatase 1-beta (PP1B). Both in vitro and in vivo validation assays demonstrate the interactions of Staufen1 and PP1B with dynein, and their colocalization with synaptic markers was altered as a result of two separate ALS-linked mutations: mSOD1(G93A) and TDP43(A315T). Taken together, we suggest a model in which dynein's interaction with Staufen1 regulates mRNA localization along the axon and the synapses, and alterations in this process may correlate with synapse disruption and ALS toxicity.
authors.affiliation: From the ‡Sagol School of Neuroscience and Department of Physiology and Pharmacology, Sackler School of Medicine and.
authors.forename: Noga
authors.initials: N
authors.lastname: Gershoni-Emek
authors.affiliation: §Blavatnik School of Computer Science, Tel Aviv University, Israel;
authors.forename: Arnon
authors.initials: A
authors.lastname: Mazza
authors.affiliation: From the ‡Sagol School of Neuroscience and Department of Physiology and Pharmacology, Sackler School of Medicine and.
authors.forename: Michael
authors.initials: M
authors.lastname: Chein
authors.affiliation: From the ‡Sagol School of Neuroscience and Department of Physiology and Pharmacology, Sackler School of Medicine and.
authors.forename: Tal
authors.initials: T
authors.lastname: Gradus-Pery
authors.affiliation: ¶Department of Biochemistry and Molecular Biology, the Uniformed Services University of Health Sciences, Bethesda, MD;
authors.forename: Xin
authors.initials: X
authors.lastname: Xiang
authors.affiliation: ‖Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, the Netherlands.
authors.forename: Ka Wan
authors.initials: KW
authors.lastname: Li
authors.affiliation: §Blavatnik School of Computer Science, Tel Aviv University, Israel;
authors.forename: Roded
authors.initials: R
authors.lastname: Sharan
authors.affiliation: From the ‡Sagol School of Neuroscience and Department of Physiology and Pharmacology, Sackler School of Medicine and eranpe@post.tau.ac.il.
authors.forename: Eran
authors.initials: E
authors.lastname: Perlson
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D056445:Cytoplasmic Dyneins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D040901:Proteomics; D016601:RNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D013569:Synapses / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013574:Synaptosomes / Q000378:metabolism / Q000473:pathology
chemical_list: D016601:RNA-Binding Proteins; C492187:Stau1 protein, mouse; D056445:Cytoplasmic Dyneins