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Hum Mol Genet. 2015 Dec 15;24(24):6886-98. doi: 10.1093/hmg/ddv389. Epub 2015 Sep 18.

Fragile X protein mitigates TDP-43 toxicity by remodeling RNA granules and restoring translation.

Author information

1
Department of Molecular and Cellular Biology, Department of Neuroscience.
2
Department of Molecular and Cellular Biology.
3
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
4
ALS Biopharma, LLC, Doylestown, PA, USA and.
5
Department of Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.
6
Department of Molecular and Cellular Biology, Department of Neuroscience, Department of Neurology, University of Arizona, Tucson, AZ, USA.
7
Department of Molecular and Cellular Biology, Department of Neuroscience, Department of Neurology, University of Arizona, Tucson, AZ, USA, zarnescu@email.arizona.edu.

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.

PMID:
26385636
PMCID:
PMC5007633
DOI:
10.1093/hmg/ddv389
[Indexed for MEDLINE]
Free PMC Article

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