FUTSCH/MAP1B mRNA is a translational target of TDP-43 and is neuroprotective in a Drosophila model of amyotrophic lateral sclerosis

Alyssa N. Coyne, Bhavani Bagevalu Siddegowda, Patricia S. Estes, Jeffrey Johannesmeyer, Tina Kovalik, Scott G. Daniel, Antony Pearson, Robert Bowser, Daniela C. Zarnescu

Research output: Contribution to journalArticlepeer-review

82 Scopus citations

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 findhigher 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.

Original languageEnglish (US)
Pages (from-to)15962-15974
Number of pages13
JournalJournal of Neuroscience
Volume34
Issue number48
DOIs
StatePublished - Nov 26 2014

Keywords

  • Microtubule stability
  • Neuromuscular junction
  • RNA metabolism

ASJC Scopus subject areas

  • Neuroscience(all)

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