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Acta Neuropathol. 2016 Nov;132(5):721-738. Epub 2016 Aug 12.

Co-regulation of mRNA translation by TDP-43 and Fragile X Syndrome protein FMRP.

Author information

1
Institute of Molecular Biology, Academia Sinica, Nankang, Taipei, 115, Taiwan.
2
Institute of Molecular Biology, Academia Sinica, Nankang, Taipei, 115, Taiwan. ckshen@imb.sinica.edu.tw.

Abstract

For proper mammalian brain development and functioning, the translation of many neuronal mRNAs needs to be repressed without neuronal activity stimulations. We have discovered that the expression of a subclass of neuronal proteins essential for neurodevelopment and neuron plasticity is co-regulated at the translational level by TDP-43 and the Fragile X Syndrome protein FMRP. Using molecular, cellular and imaging approaches, we show that these two RNA-binding proteins (RBP) co-repress the translation initiation of Rac1, Map1b and GluR1 mRNAs, and consequently the hippocampal spinogenesis. The co-repression occurs through binding of TDP-43 to mRNA(s) at specific UG/GU sequences and recruitment of the inhibitory CYFIP1-FMRP complex by its glycine-rich domain. This novel regulatory scenario could be utilized to silence a significant portion of around 160 common target mRNAs of the two RBPs. The study establishes a functional/physical partnership between FMRP and TDP-43 that mechanistically links several neurodevelopmental disorders and neurodegenerative diseases.

KEYWORDS:

CYFIP1; FISH; FMRP; Immunofluorescence staining; Live cell imaging; Polysome profile; RNA-IP; TDP-43; Translation initiation

PMID:
27518042
PMCID:
PMC5073124
DOI:
10.1007/s00401-016-1603-8
[Indexed for MEDLINE]
Free PMC Article

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