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@ARTICLE{Brievac:155270,
      author       = {Briševac, Dušica and Scholz, Ralf and Du, Dan and
                      Elagabani, Mohammad Nael and Köhr, Georg and Kornau,
                      Hans-Christian},
      title        = {{T}he small {GTP}ase {A}rf6 is dysregulated in a mouse
                      model for fragile {X} syndrome},
      journal      = {Journal of neurochemistry},
      volume       = {157},
      number       = {3},
      issn         = {1471-4159},
      address      = {Oxford},
      publisher    = {Wiley-Blackwell},
      reportid     = {DZNE-2021-00550},
      pages        = {666 - 683},
      year         = {2021},
      abstract     = {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.},
      keywords     = {ADP-Ribosylation Factor 6 / ADP-Ribosylation Factors:
                      metabolism / Actin Cytoskeleton: metabolism / Animals /
                      Dendritic Spines: ultrastructure / Fragile X Mental
                      Retardation Protein: genetics / Fragile X Mental Retardation
                      Protein: metabolism / Fragile X Syndrome: genetics / Fragile
                      X Syndrome: metabolism / Guanine Nucleotide Exchange
                      Factors: genetics / Guanine Nucleotide Exchange Factors:
                      metabolism / Guanosine Triphosphate: metabolism / Mice /
                      Mice, Inbred C57BL / Mice, Knockout / Nerve Tissue Proteins:
                      genetics / Neuronal Plasticity: genetics / Neurons:
                      metabolism / RNA Interference / Receptors, Metabotropic
                      Glutamate: metabolism / Synaptosomes: metabolism},
      cin          = {AG Schmitz 1},
      ddc          = {610},
      cid          = {I:(DE-2719)1810004},
      pnm          = {351 - Brain Function (POF4-351)},
      pid          = {G:(DE-HGF)POF4-351},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:33125726},
      pubmed       = {33125726},
      doi          = {10.1111/jnc.15230},
      url          = {https://pub.dzne.de/record/155270},
}