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000155270 0247_ $$2doi$$a10.1111/jnc.15230
000155270 0247_ $$2ISSN$$a0022-3042
000155270 0247_ $$2ISSN$$a1471-4159
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000155270 0247_ $$2pmid$$a33125726
000155270 037__ $$aDZNE-2021-00550
000155270 041__ $$aEnglish
000155270 082__ $$a610
000155270 1001_ $$aBriševac, Dušica$$b0
000155270 245__ $$aThe small GTPase Arf6 is dysregulated in a mouse model for fragile X syndrome
000155270 260__ $$aOxford$$bWiley-Blackwell$$c2021
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000155270 520__ $$aFragile X syndrome (FXS), the most common inherited cause of intellectual disability, results from silencing of the fragile X mental retardation gene 1 (FMR1). The analyses of FXS patients’ brain autopsies revealed an increased density of immature dendritic spines in cortical areas. We hypothesize that the small GTPase Arf6, an actin regulator critical for the development of glutamatergic synapses and dendritic spines, is implicated in FXS. Here, we determined the fraction of active, GTP-bound Arf6 in cortical neuron cultures and synaptoneurosomes from Fmr1 knockout mice, measured actin polymerization in neurons expressing Arf6 mutants with variant GTP- or GDP-binding properties, and recorded hippocampal long-term depression induced by metabotropic glutamate receptors (mGluR-LTD) in acute brain slices. We detected a persistently elevated Arf6 activity, a loss of Arf6 sensitivity to synaptic stimulation and an increased Arf6-dependent dendritic actin polymerization in mature Fmr1 knockout neurons. Similar imbalances in Arf6-GTP levels and actin filament assembly were caused in wild-type neurons by RNAi-mediated depletion of the postsynaptic Arf6 guanylate exchange factors IQSEC1 (BRAG2) or IQSEC2 (BRAG1). Targeted deletion of Iqsec1 in hippocampal neurons of 3-week-old mice interfered with mGluR-LTD in wild-type, but not in Fmr1 knockout mice. Collectively, these data suggest an aberrant Arf6 regulation in Fmr1 knockout neurons with consequences for the actin cytoskeleton, spine morphology, and synaptic plasticity. Moreover, FXS and syndromes caused by genetic variants in IQSEC1 and IQSEC2 share intellectual disabilities and developmental delay as main symptoms. Therefore, dysregulation of Arf6 may contribute to the cognitive impairment in FXS. 
000155270 536__ $$0G:(DE-HGF)POF4-351$$a351 - Brain Function (POF4-351)$$cPOF4-351$$fPOF IV$$x0
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000155270 650_2 $$2MeSH$$aADP-Ribosylation Factor 6
000155270 650_2 $$2MeSH$$aADP-Ribosylation Factors: metabolism
000155270 650_2 $$2MeSH$$aActin Cytoskeleton: metabolism
000155270 650_2 $$2MeSH$$aAnimals
000155270 650_2 $$2MeSH$$aDendritic Spines: ultrastructure
000155270 650_2 $$2MeSH$$aFragile X Mental Retardation Protein: genetics
000155270 650_2 $$2MeSH$$aFragile X Mental Retardation Protein: metabolism
000155270 650_2 $$2MeSH$$aFragile X Syndrome: genetics
000155270 650_2 $$2MeSH$$aFragile X Syndrome: metabolism
000155270 650_2 $$2MeSH$$aGuanine Nucleotide Exchange Factors: genetics
000155270 650_2 $$2MeSH$$aGuanine Nucleotide Exchange Factors: metabolism
000155270 650_2 $$2MeSH$$aGuanosine Triphosphate: metabolism
000155270 650_2 $$2MeSH$$aMice
000155270 650_2 $$2MeSH$$aMice, Inbred C57BL
000155270 650_2 $$2MeSH$$aMice, Knockout
000155270 650_2 $$2MeSH$$aNerve Tissue Proteins: genetics
000155270 650_2 $$2MeSH$$aNeuronal Plasticity: genetics
000155270 650_2 $$2MeSH$$aNeurons: metabolism
000155270 650_2 $$2MeSH$$aRNA Interference
000155270 650_2 $$2MeSH$$aReceptors, Metabotropic Glutamate: metabolism
000155270 650_2 $$2MeSH$$aSynaptosomes: metabolism
000155270 7001_ $$00000-0002-4542-2886$$aScholz, Ralf$$b1
000155270 7001_ $$aDu, Dan$$b2
000155270 7001_ $$00000-0002-8611-3975$$aElagabani, Mohammad Nael$$b3
000155270 7001_ $$00000-0001-6768-3545$$aKöhr, Georg$$b4
000155270 7001_ $$0P:(DE-2719)2811900$$aKornau, Hans-Christian$$b5$$eLast author$$udzne
000155270 773__ $$0PERI:(DE-600)2020528-4$$a10.1111/jnc.15230$$gVol. 157, no. 3, p. 666 - 683$$n3$$p666 - 683$$tJournal of neurochemistry$$v157$$x1471-4159$$y2021
000155270 8564_ $$uhttps://onlinelibrary.wiley.com/doi/full/10.1111/jnc.15230
000155270 8564_ $$uhttps://pub.dzne.de/record/155270/files/7832.pdf$$yOpenAccess
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