Khandjian, E. W. et al. Biochemical evidence for the association of fragile X mental retardation protein with brain polyribosomal ribonucleoparticles. Proc. Natl Acad. Sci. USA 101, 13357-13362

Unité de Recherche en Génétique Humaine et Moléculaire, Centre de Recherche Hôpital Saint-François d'Assise, Centre Hospitalier Universitaire de Québec, Québec, QC, Canada G1L 3L5.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 10/2004; 101(36):13357-62. DOI: 10.1073/pnas.0405398101
Source: PubMed


Fragile X syndrome is caused by the absence of the fragile X mental retardation protein (FMRP). This RNA-binding protein is widely expressed in human and mouse tissues, and it is particularly abundant in the brain because of its high expression in neurons, where it localizes in the cell body and in granules throughout dendrites. Although FMRP is thought to regulate trafficking of repressed mRNA complexes and to influence local protein synthesis in synapses, it is not known whether it has additional functions in the control of translation in the cell body. Here, we have used recently developed approaches to investigate whether FMRP is associated with the translation apparatus. We demonstrate that, in the brain, FMRP is present in actively translating polyribosomes, and we show that this association is acutely sensitive to the type of detergent required to release polyribosomes from membranous structures. In addition, proteomic analyses of purified brain polyribosomes reveal the presence of several RNA-binding proteins that, similarly to FMRP, have been previously localized in neuronal granules. Our findings highlight the complex roles of FMRP both in actively translating polyribosomes and in repressed trafficking ribonucleoparticle granules.

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    • "One well-characterized function of this RNA-binding protein is to suppress the translation of these target mRNAs. Through mechanisms that are not fully understood, neuronal activity can release the suppression of some mRNAs (Khandjian et al., 2004; Stefani et al., 2004), leading to an activity-dependent increase in protein synthesis in synaptosomal regions (Bassell and Warren, 2008). FMRP binds to polyribosomes and specific mRNAs in neuronal dendrites, leading to the concept that it regulates local translation at these sites. "
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    ABSTRACT: The sodium-activated potassium KNa channels Slack and Slick are encoded by KCNT1 and KCNT2, respectively. These channels are found in neurons throughout the brain, and are responsible for a delayed outward current termed I KNa. These currents integrate into shaping neuronal excitability, as well as adaptation in response to maintained stimulation. Abnormal Slack channel activity may play a role in Fragile X syndrome, the most common cause for intellectual disability and inherited autism. Slack channels interact directly with the fragile X mental retardation protein (FMRP) and I KNa is reduced in animal models of Fragile X syndrome that lack FMRP. Human Slack mutations that alter channel activity can also lead to intellectual disability, as has been found for several childhood epileptic disorders. Ongoing research is elucidating the relationship between mutant Slack channel activity, development of early onset epilepsies and intellectual impairment. This review describes the emerging role of Slack channels in intellectual disability, coupled with an overview of the physiological role of neuronal I KNa currents.
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    • "A recent study using double FMR1/BC1 KO mice has definitively shown that FMRP and BC1 cannot belong to the same complex even if they are likely to modulate common target RNAs via independent mechanisms (Zhong et al., 2010). Furthermore, since more than 80% of the FMRP pool is located on translating polyribosomes, the role of a putative CYFIP-FMRP containing initiation complex in regulating initiation of translation is very unlikely to have an impact on FMRP function (Corbin et al., 1997; Feng et al., 1997; Khandjian et al., 2004; Stefani et al., 2004; Aschrafi et al., 2005; Darnell et al., 2011). It is also important to underline that the interaction of CYFIP1/2 via FMRP with polyribosomes was shown, suggesting that CYFIP can also modulate the main function of FMRP when it is associated to actively translating polyribosomes (Schenck et al., 2001). "
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    ABSTRACT: Intellectual disability (ID) and autism spectrum disorders (ASDs) have in common alterations in some brain circuits and brain abnormalities, such as synaptic transmission and dendritic spines morphology. Recent studies have indicated a differential expression for specific categories of genes as a cause for both types of disease, while an increasing number of genes is recognized to produce both disorders. An example is the Fragile X mental retardation gene 1 (FMR1), whose silencing causes the Fragile X syndrome, the most common form of ID and autism, also characterized by physical hallmarks. Fragile X mental retardation protein (FMRP), the protein encoded by FMR1, is an RNA-binding protein with an important role in translational control. Among the interactors of FMRP, CYFIP1/2 (cytoplasmic FMRP interacting protein) proteins are good candidates for ID and autism, on the bases of their genetic implication and functional properties, even if the precise functional significance of the CYFIP/FMRP interaction is not understood yet. CYFIP1 and CYFIP2 represent a link between Rac1, the WAVE (WAS protein family member) complex and FMRP, favoring the cross talk between actin polymerization and translational control.
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    • "Gehrke et al. reported that LRRK2 co-localized with Ago1 in polysomes, an active site of miRNA function and protein translation [35], [36]. In the mouse brain, and as expected, Ago2, co-localized mainly with the polysome marker FMRP (Fig. S4) [37]. Subsequent detailed analysis demonstrated that LRRK2 and Ago2 co-localized partly in free ribonucleoprotein proteins (RNP) fractions (Fig. 4B). "
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    ABSTRACT: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of genetic Parkinson's disease (PD). The biological function of LRRK2 and how mutations lead to disease remain poorly defined. It has been proposed that LRRK2 could function in gene transcription regulation; however, this issue remains controversial. Here, we investigated in parallel gene and microRNA (miRNA) transcriptome profiles of three different LRRK2 mouse models. Striatal tissue was isolated from adult LRRK2 knockout (KO) mice, as well as mice expressing human LRRK2 wildtype (hLRRK2-WT) or the PD-associated R1441G mutation (hLRRK2-R1441G). We identified a total of 761 genes and 24 miRNAs that were misregulated in the absence of LRRK2 when a false discovery rate of 0.2 was applied. Notably, most changes in gene expression were modest (i.e., <2 fold). By real-time quantitative RT-PCR, we confirmed the variations of selected genes (e.g., adra2, syt2, opalin) and miRNAs (e.g., miR-16, miR-25). Surprisingly, little or no changes in gene expression were observed in mice expressing hLRRK2-WT or hLRRK2-R1441G when compared to non-transgenic controls. Nevertheless, a number of miRNAs were misexpressed in these models. Bioinformatics analysis identified several miRNA-dependent and independent networks dysregulated in LRRK2-deficient mice, including PD-related pathways. These results suggest that brain LRRK2 plays an overall modest role in gene transcription regulation in mammals; however, these effects seem context and RNA type-dependent. Our data thus set the stage for future investigations regarding LRRK2 function in PD development.
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