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

Pritha Majumder, Jen Fei Chu, Biswanath Chatterjee, Krishna B.S. Swamy, Che Kun James Shen

Research output: Contribution to journalArticle

37 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)721-738
Number of pages18
JournalActa Neuropathologica
Volume132
Issue number5
DOIs
Publication statusPublished - Nov 1 2016
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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