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        Impaired synaptic signalling involved in fragile X syndrome

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        Final Review FXS synaps signalling - Kes Kloosterhuis 5980232.pdf (680.1Kb)
        Publication date
        2023
        Author
        Kloosterhuis, Kes
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        Summary
        Fragile X syndrome (FXS) is a monogenetic disorder caused by loss of function of the Fmr1 gene encoding the RNA-binding protein FMRP, which is known to associate with ribosomes and act as a translational regulator. FXS shows a lot of overlapping cellular features with autism spectrum disorders (ASDs), including aberrancies in synapse number, morphology and function. This review aims to provide an overview of synaptic signalling pathways involved in FXS in the context of recent findings, and increase the understanding of the interplay of synaptic processes at hand to aid future research and FXS treatment development. Important mechanisms dysregulated in FXS synapses include metabotropic glutamate receptor (mGluR) mediated long-term depression (LTD), which is the focus of the popular mGluR theory of FXS, association and functioning of FMRP-containing translation complexes and competing regulatory complexes including the WAVE complex, various forms of synaptic plasticity involving mGluRs, N-methyl-D-aspartate receptors (NMDARs), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and γ-aminobutyric acid receptors (GABARs) leading to a disturbed excitation-inhibition balance and actin cytoskeleton remodelling. FMRP deficiency leads to exaggerated dendritic synthesis of proteins involved in these processes which underly functional and structural synaptic plasticity, inducing FXS features including an increase in immature thin long spines with a lower postsynaptic density. Current FXS treatment development shows limited results, illustrating the need for a shift towards iPSC-derived models that can account for heterogeneity among patients and improve drug screenings, development of new treatment strategies and fundamental research on synaptic disease mechanisms underlying FXS.
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        https://studenttheses.uu.nl/handle/20.500.12932/43500
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