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001     155270
005     20240320115508.0
024 7 _ |a pmid:33125726
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024 7 _ |a 10.1111/jnc.15230
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024 7 _ |a 1471-4159
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024 7 _ |a 33125726
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037 _ _ |a DZNE-2021-00550
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Briševac, Dušica
|b 0
245 _ _ |a The small GTPase Arf6 is dysregulated in a mouse model for fragile X syndrome
260 _ _ |a Oxford
|c 2021
|b Wiley-Blackwell
336 7 _ |a article
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520 _ _ |a Fragile 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.
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650 _ 2 |a ADP-Ribosylation Factor 6
|2 MeSH
650 _ 2 |a ADP-Ribosylation Factors: metabolism
|2 MeSH
650 _ 2 |a Actin Cytoskeleton: metabolism
|2 MeSH
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Dendritic Spines: ultrastructure
|2 MeSH
650 _ 2 |a Fragile X Mental Retardation Protein: genetics
|2 MeSH
650 _ 2 |a Fragile X Mental Retardation Protein: metabolism
|2 MeSH
650 _ 2 |a Fragile X Syndrome: genetics
|2 MeSH
650 _ 2 |a Fragile X Syndrome: metabolism
|2 MeSH
650 _ 2 |a Guanine Nucleotide Exchange Factors: genetics
|2 MeSH
650 _ 2 |a Guanine Nucleotide Exchange Factors: metabolism
|2 MeSH
650 _ 2 |a Guanosine Triphosphate: metabolism
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Mice, Inbred C57BL
|2 MeSH
650 _ 2 |a Mice, Knockout
|2 MeSH
650 _ 2 |a Nerve Tissue Proteins: genetics
|2 MeSH
650 _ 2 |a Neuronal Plasticity: genetics
|2 MeSH
650 _ 2 |a Neurons: metabolism
|2 MeSH
650 _ 2 |a RNA Interference
|2 MeSH
650 _ 2 |a Receptors, Metabotropic Glutamate: metabolism
|2 MeSH
650 _ 2 |a Synaptosomes: metabolism
|2 MeSH
700 1 _ |a Scholz, Ralf
|0 0000-0002-4542-2886
|b 1
700 1 _ |a Du, Dan
|b 2
700 1 _ |a Elagabani, Mohammad Nael
|0 0000-0002-8611-3975
|b 3
700 1 _ |a Köhr, Georg
|0 0000-0001-6768-3545
|b 4
700 1 _ |a Kornau, Hans-Christian
|0 P:(DE-2719)2811900
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773 _ _ |a 10.1111/jnc.15230
|g Vol. 157, no. 3, p. 666 - 683
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|t Journal of neurochemistry
|v 157
|y 2021
|x 1471-4159
856 4 _ |u https://onlinelibrary.wiley.com/doi/full/10.1111/jnc.15230
856 4 _ |u https://pub.dzne.de/record/155270/files/7832.pdf
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910 1 _ |a Deutsches Zentrum für Neurodegenerative Erkrankungen
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