Show simple item record

dc.rights.licenseCC-BY-NC-ND
dc.contributor.advisorKas, M.J.H.
dc.contributor.authorLegerstee, K.
dc.date.accessioned2011-07-21T17:02:26Z
dc.date.available2011-07-21
dc.date.available2011-07-21T17:02:26Z
dc.date.issued2011
dc.identifier.urihttps://studenttheses.uu.nl/handle/20.500.12932/7500
dc.description.abstractThis literature study investigates the role Cyfip1 could play in the pathophysiology of the Fragile X Syndrome (FXS). FXS, the most common form of mental retardation, is caused by disruptions to the Fmr1 gene. In all cases except one FXS is caused by a loss of expression of the protein encoded for by Fmr1, FMRP, most commonly due to a CGG-repeat expansion resulting in excessive methylation of FMRP. In the single exception a point mutation in the FMR1 gene specifically impairs the ability of FMRP to associate with polyribosomes, while leaving its ability to bind (m)RNA molecules in vivo intact (De Boulle et al., 1993; Feng et al., 1997a; Siomi et al.,1994). It results in an especially severe form of FXS. Suggesting that, although FMRP has a number of different functions in cells it is its role in the regulation of (local) mRNA translation as a binding partner of polyribosomes, mainly repressing the translation of its target mRNAs, that is crucial to the pathophysiology of FXS (Laggerbauer et al., 2001; Lu et al., 2004). As a mechanistic explanation of the pathophysiology of FXS the ‘mGluR theory of fragile X’ is most commonly accepted (Bear et al., 2004).It also points to the role of FMRP in the regulation of local mRNA translation as critical for the pathophysiology of FXS. According to this theory the activation of group 1 metabotropic glutamate receptors (mGluRs) at dendrites stimulates the local translation of mRNAs that are responsible for the functional effects of mGluR-signalling as well as of FMRP. The FMRP inhibits the further local translation of these mRNAs, serving as a form of end-product inhibition for the mGluR-signalling. In the absence of FMRP, as in FXS, the inhibition by FMRP falls away leading to an exaggeration of all local protein synthesis-dependent effects of mGluR-signalling, proposed to be the underlying cause of the diverse symptoms of FXS. The Fmr1 knockout mouse model of FXS displays a multifaceted phenotype that is generally consist with the symptoms seen in FXS patients and includes phenotypes analogous to the physical, neurological, structural and behavioural characteristics of FXS in humans (Bakker et al., 1994). However, the hallmark mental retardation appears to be more effectively replicated in the dFmr1 loss of function Drosophila FXS model (Bolduc et al., 2008; Choi et al., 2010; McBride et al., 2005; Wan et al., 2000). In support of the ‘mGluR theory of FXS’ it has been demonstrated that several local protein synthesis-dependent effects of mGluR-signalling are enhanced in a range of different brain structures in animal models of FXS. Through these effects the theory can be envisioned to explain most symptoms of FXS. Most convincingly, the relevance of excessive group1 mGluR-signalling to FXS symptoms is directly demonstrated by the significant rescue of neurological, physical and cellular aspects of FXS in mice with complete knockout of Fmr1 as well as a 50% knockdown of Grm5, the gene coding for the group 1 metabotropic glutamate receptor mGluR5 (Dolen et al., 2007). Similarly, pharmacological inhibition of group 1 mGluR-signalling in the Fmr1 knockout mouse significantly rescues phenotypes analogous to neurological, cellular and behavioural characteristics of FXS (Chuang et al., 2005; de Vrij et al., 2008; Levenga et al., 2011; Su et al., 2011; Yan et al., 2005). In the Drosophila model inhibiting group 1 mGluR signalling was also able to rescue the cognitive deficits seen in these flies (Bolduc et al., 2008; Choi et al., 2010; McBride et al., 2005). Establishing the validity of the main points of the ‘mGluR theory of FXS’, including the assumption that the role of FMRP in local protein synthesis is crucial for the pathophysiology of FXS. Cyfip1 is a known cytoplasmic interactor of FMRP (Schenck et al., 2001). Genetic studies have provided some data suggesting that Cyfip1 might play a role in some of the symptoms of FXS, especially its autistic features (Butler et al., 2004; Doornbos et al., 2009; Milner et al., 2005; Murthy et al., 2007; Nishimura et al., 2007; Nowicki et al., 2007; van der Zwaag et al., 2010). However, it is the finding that Cyfip1 as an eukaryotic initiation factor 4E Binding Protein (4E-BP) mediates the inhibition of local mRNA translation by FMRP, that convincingly points to a crucial role of Cyfip1 in the pathophysiology of FXS (Napoli et al., 2008). For many of the FMRP-target mRNAs, which would be expected to include mRNAs crucial for many of the local protein-synthesis dependent effects of mGluR-signalling, it is in fact Cyfip1 that is mediating the effects of FMRP on local mRNA translation. Placing CYFIP1, just like FMRP, at the heart of the ‘mGluR theory of FXS’ and warranting a much more extensive investigation into the role of Cyfip1 in the pathophysiology of FXS.
dc.description.sponsorshipUtrecht University
dc.format.extent135575 bytes
dc.format.mimetypeapplication/msword
dc.language.isoen
dc.titleCytoplasmic FMRP Interacting Protein 1 (CYFIP1) - A key player in the pathophysiology of the Fragile X Syndrome?
dc.type.contentMaster Thesis
dc.rights.accessrightsOpen Access
dc.subject.keywordsFragile X Syndrome, Cyfip1, mGluR theory of fragile X
dc.subject.courseuuNeuroscience and Cognition


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record