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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1603-8) contains supplementary material, which is available to authorized users.

Multifarious Functions of the Fragile X Mental Retardation Protein

“…However, it is clear that FMRP also binds many non-synaptic transcripts, and that translational regulation of most synaptic transcripts does not occur exclusively (or even predominantly) locally at synapses [5,12,30]. Although many mechanisms have been proposed to explain the RNA-binding specificity of FMRP, including both secondary structure (G-quartet) and consensus nucleotide sequences [34], there is little compelling evidence for any universal mechanism [35]. Therefore, it remains unclear by which mechanism(s) FMRP specifically binds target mRNAs, or which mRNAs contribute predominantly to FXS neuropathology.…”

Epitranscriptome and FMRP Regulated mRNA Translation

“…A functional link between these two RBPs in dendritic translation regulation has also been elucidated [100,101]. In another study, overexpression of TDP-43 inhibited translation of Futsch (Drosophila homolog of Map1b) mRNA in motor neurons [102], which was re-activated by overexpression of FMRP [103].…”

“…Recently, it has been established that FMRP and Frontotemporal Lobar Dementia (FTLD)/ALS pathology related protein TDP-43 physically interact and associate with same mRNPs [100]. A functional link between these two RBPs in dendritic translation regulation has also been elucidated [100,101].…”

“…It has been established that TDP-43 recruits the FMRP-CYFIP1-eIF4E inhibitory complex to the target mRNAs present at dendrites, thereby repressing initiation of translation [100]. Thus TDP-43 acts as an adaptor protein between target mRNAs and FMRP.…”

“…A significant portion of these mRNAs might be co-regulated by FMRP and TDP-43 at the translational level. Interestingly, the above mentioned 160 common targets of FMRP and TDP-43 also include candidate genes for Autism Spectrum Disorder (ASD; e.g., Rac1, Mapk1, Reln, and Shank3), Alzheimer's disease (AD; e.g., Ank1, App, and Apoe) and Schizophrenia (e.g., Grin2b and Gsk3b) indicating that loss-of-function of either of these two RBPs might develop similar phenotypes [100].…”