title: Futsch/MAP1B mRNA is a translational target of TDP-43 and is neuroprotective in a Drosophila model of amyotrophic lateral sclerosis.
abstract: TDP-43 is an RNA-binding protein linked to amyotrophic lateral sclerosis (ALS) that is known to regulate the splicing, transport, and storage of specific mRNAs into stress granules. Although TDP-43 has been shown to interact with translation factors, its role in protein synthesis remains unclear, and no in vivo translation targets have been reported to date. Here we provide evidence that TDP-43 associates with futsch mRNA in a complex and regulates its expression at the neuromuscular junction (NMJ) in Drosophila. In the context of TDP-43-induced proteinopathy, there is a significant reduction of futsch mRNA at the NMJ compared with motor neuron cell bodies where we find higher levels of transcript compared with controls. TDP-43 also leads to a significant reduction in Futsch protein expression at the NMJ. Polysome fractionations coupled with quantitative PCR experiments indicate that TDP-43 leads to a futsch mRNA shift from actively translating polysomes to nontranslating ribonuclear protein particles, suggesting that in addition to its effect on localization, TDP-43 also regulates the translation of futsch mRNA. We also show that futsch overexpression is neuroprotective by extending life span, reducing TDP-43 aggregation, and suppressing ALS-like locomotor dysfunction as well as NMJ abnormalities linked to microtubule and synaptic stabilization. Furthermore, the localization of MAP1B, the mammalian homolog of Futsch, is altered in ALS spinal cords in a manner similar to our observations in Drosophila motor neurons. Together, our results suggest a microtubule-dependent mechanism in motor neuron disease caused by TDP-43-dependent alterations in futsch mRNA localization and translation in vivo.
authors.affiliation: Departments of Molecular and Cellular Biology, Neuroscience, and.
authors.forename: Alyssa N
authors.initials: AN
authors.lastname: Coyne
authors.affiliation: Departments of Molecular and Cellular Biology.
authors.forename: Bhavani Bagevalu
authors.initials: BB
authors.lastname: Siddegowda
authors.affiliation: Departments of Molecular and Cellular Biology.
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Estes
authors.affiliation: Departments of Molecular and Cellular Biology.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Johannesmeyer
authors.affiliation: Divisions of Neurobiology and Neurology, Barrow Neurological Institute, Phoenix, Arizona 85013.
authors.forename: Tina
authors.initials: T
authors.lastname: Kovalik
authors.affiliation: Departments of Molecular and Cellular Biology.
authors.forename: Scott G
authors.initials: SG
authors.lastname: Daniel
authors.affiliation: Departments of Molecular and Cellular Biology.
authors.forename: Antony
authors.initials: A
authors.lastname: Pearson
authors.affiliation: Divisions of Neurobiology and Neurology, Barrow Neurological Institute, Phoenix, Arizona 85013.
authors.forename: Robert
authors.initials: R
authors.lastname: Bowser
authors.affiliation: Departments of Molecular and Cellular Biology, Neuroscience, and Neurology, University of Arizona, Tucson, Arizona 85721, and zarnescu@email.arizona.edu.
authors.forename: Daniela C
authors.identifier: http://orcid.org/0000-0002-9607-0139
authors.initials: DC
authors.lastname: Zarnescu
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control; D000818:Animals; D030801:Animals, Genetically Modified; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D004195:Disease Models, Animal; D004330:Drosophila; D029721:Drosophila Proteins / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D018390:Gene Targeting / Q000379:methods; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000235:genetics*; D008875:Middle Aged; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C475491:MAP1B protein, human; D008869:Microtubule-Associated Proteins; D012333:RNA, Messenger; C000589036:TBPH protein, Drosophila; C409635:futsch protein, Drosophila
keywords: RNA metabolism; microtubule stability; neuromuscular junction