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


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.

SUBMITTER: Majumder P 

PROVIDER: S-EPMC5073124 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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

Majumder Pritha P   Chu Jen-Fei JF   Chatterjee Biswanath B   Swamy Krishna B S KB   Shen Che-Kun James CJ  

Acta neuropathologica 20160812 5


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 transla  ...[more]

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