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Neurodegeneration-associated TDP-43 interacts with fragile X mental retardation protein (FMRP)/Staufen (STAU1) and regulates SIRT1 expression in neuronal cells.

ABSTRACT: Despite the identification of the 43 kDa transactive response DNA-binding protein (TDP-43) as a major pathological signatory protein in a wide range of neurodegenerative diseases, the mechanistic role of TDP-43 in neurodegenerative disorders is still poorly understood. Here, we report that TDP-43 is physically associated with fragile X mental retardation protein (FMRP) and Staufen (STAU1) to form a functional complex. Differential microarray analysis revealed that the expression of a collection of functionally important genes including Sirtuin (SIRT1) is regulated by this complex. RNA-immunoprecipitation (RIP) and RNA pull-down assays demonstrated that TDP-43/FMRP/STAU1 specifically binds to the 3'-UTR of SIRT1 mRNA, and that knockdown the expression of any one of these three proteins resulted in the reduction of SIRT1 mRNA and protein. SIRT1 is implicated in double-stranded DNA break repair and is required for cell survival. Indeed, depletion of TDP-43/FMRP/STAU1 sensitizes cells to apoptosis and DNA damages. Collectively, our results revealed a molecular mechanism for the cellular function of TDP-43 and might shed new light on the understanding of the mechanistic role of TDP-43 in neurodegenerative diseases.

SUBMITTER: Yu Z

PROVIDER: S-EPMC3391095 | biostudies-literature |

REPOSITORIES: biostudies-literature

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The Fragile X Mental Retardation Protein (FMRP) controls diacylglycerol kinase in neurons

Project description:In this study, we sought to identify the mRNAs associated to FMRP protein in mouse cortical neuron using a cross linking immunoprecipitation and microarray (CLIP-microarray). The mRNAs crosslinked at 254 nm to FMRP in mouse cortical neurons cultured 8 days in vitro (8 DIV) were immunoprecipitated with H120 anti-FMRP (Santa Cruz) and reverse transcribed to labeled cDNAs with Ovation Pico WTA system V2 (Nugen) and hybridized on Mouse Gene 1.0ST (Affymetrix) We analyzed total RNA (Input) and FMRP-CLIPed RNA (Clip) from 10 primary cortical neuron mouse cultures (5 Wt Input, 5 FMR1-KO Input, 5 Wt Clip, 5 FMR1-KO Clip). Array data was processed by Affymetrix Exon Array Computational Tool. No technical replicates were performed.

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Project description:Expansion of the CGG.CCG-repeat tract in the 5' UTR of the FMR1 gene to >200 repeats leads to heterochromatinization of the promoter and gene silencing. This results in Fragile X syndrome (FXS), the most common heritable form of mental retardation. The mechanism of gene silencing is unknown. We report here that a Class III histone deacetylase, SIRT1, plays an important role in this silencing process and show that the inhibition of this enzyme produces significant gene reactivation. This contrasts with the much smaller effect of inhibitors like trichostatin A (TSA) that inhibit Class I, II and IV histone deacetylases. Reactivation of silenced FMR1 alleles was accompanied by an increase in histone H3 lysine 9 acetylation as well as an increase in the amount of histone H4 that is acetylated at lysine 16 (H4K16) by the histone acetyltransferase, hMOF. DNA methylation, on the other hand, is unaffected. We also demonstrate that deacetylation of H4K16 is a key downstream consequence of DNA methylation. However, since DNA methylation inhibitors require DNA replication in order to be effective, SIRT1 inhibitors may be more useful for FMR1 gene reactivation in post-mitotic cells like neurons where the effect of the gene silencing is most obvious.

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