title: Fragile X protein mitigates TDP-43 toxicity by remodeling RNA granules and restoring translation.
abstract: RNA dysregulation is a newly recognized disease mechanism in amyotrophic lateral sclerosis (ALS). Here we identify Drosophila fragile X mental retardation protein (dFMRP) as a robust genetic modifier of TDP-43-dependent toxicity in a Drosophila model of ALS. We find that dFMRP overexpression (dFMRP OE) mitigates TDP-43 dependent locomotor defects and reduced lifespan in Drosophila. TDP-43 and FMRP form a complex in flies and human cells. In motor neurons, TDP-43 expression increases the association of dFMRP with stress granules and colocalizes with polyA binding protein in a variant-dependent manner. Furthermore, dFMRP dosage modulates TDP-43 solubility and molecular mobility with overexpression of dFMRP resulting in a significant reduction of TDP-43 in the aggregate fraction. Polysome fractionation experiments indicate that dFMRP OE also relieves the translation inhibition of futsch mRNA, a TDP-43 target mRNA, which regulates neuromuscular synapse architecture. Restoration of futsch translation by dFMRP OE mitigates Futsch-dependent morphological phenotypes at the neuromuscular junction including synaptic size and presence of satellite boutons. Our data suggest a model whereby dFMRP is neuroprotective by remodeling TDP-43 containing RNA granules, reducing aggregation and restoring the translation of specific mRNAs in motor neurons.
authors.affiliation: Department of Molecular and Cellular Biology, Department of Neuroscience.
authors.forename: Alyssa N
authors.initials: AN
authors.lastname: Coyne
authors.affiliation: Department of Molecular and Cellular Biology.
authors.forename: Shizuka B
authors.initials: SB
authors.lastname: Yamada
authors.affiliation: Department of Molecular and Cellular Biology.
authors.forename: Bhavani Bagevalu
authors.initials: BB
authors.lastname: Siddegowda
authors.affiliation: Department of Molecular and Cellular Biology.
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Estes
authors.affiliation: Department of Molecular and Cellular Biology.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Zaepfel
authors.affiliation: Department of Molecular and Cellular Biology.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Johannesmeyer
authors.affiliation: Department of Molecular and Cellular Biology, Department of Neuroscience.
authors.forename: Donovan B
authors.initials: DB
authors.lastname: Lockwood
authors.affiliation: Department of Molecular and Cellular Biology.
authors.forename: Linh T
authors.initials: LT
authors.lastname: Pham
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Hart
authors.affiliation: ALS Biopharma, LLC, Doylestown, PA, USA and.
authors.forename: Joel A
authors.initials: JA
authors.lastname: Cassel
authors.affiliation: Department of Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Freibaum
authors.affiliation: Department of Molecular and Cellular Biology, Department of Neuroscience, Department of Neurology, University of Arizona, Tucson, AZ, USA.
authors.forename: Ashley V
authors.initials: AV
authors.lastname: Boehringer
authors.affiliation: Department of Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: J Paul
authors.initials: JP
authors.lastname: Taylor
authors.affiliation: ALS Biopharma, LLC, Doylestown, PA, USA and.
authors.forename: Allen B
authors.initials: AB
authors.lastname: Reitz
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Gitler
authors.affiliation: Department of Molecular and Cellular Biology, Department of Neuroscience, Department of Neurology, University of Arizona, Tucson, AZ, USA, zarnescu@email.arizona.edu.
authors.forename: Daniela C
authors.initials: DC
authors.lastname: Zarnescu
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics; D004331:Drosophila melanogaster; D051860:Fragile X Messenger Ribonucleoprotein 1; D055785:Gene Knockdown Techniques; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000235:genetics; D009469:Neuromuscular Junction / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009498:Neurotoxins / Q000378:metabolism; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism; D012995:Solubility; D014178:Translocation, Genetic
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D051860:Fragile X Messenger Ribonucleoprotein 1; D008869:Microtubule-Associated Proteins; D009498:Neurotoxins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C467328:FMR1 protein, Drosophila; C000598624:TARDBP protein, human; C409635:futsch protein, Drosophila