The small GTPase Arf6 is dysregulated in a mouse model for fragile X syndrome

Autor: Georg Köhr, Dušica Briševac, Dan Du, Ralf Scholz, Mohammad Nael Elagabani, Hans-Christian Kornau
Rok vydání: 2020
Předmět:
0301 basic medicine
Dendritic spine
metabolism [Fragile X Syndrome]
genetics [Neuronal Plasticity]
Receptors
Metabotropic Glutamate
Biochemistry
Fragile X Mental Retardation Protein
Mice
0302 clinical medicine
Postsynaptic potential
Guanine Nucleotide Exchange Factors
metabolism [Actin Cytoskeleton]
genetics [Nerve Tissue Proteins]
Mice
Knockout
Neurons
Neuronal Plasticity
ADP-Ribosylation Factors
metabolism [Fragile X Mental Retardation Protein]
genetics [Guanine Nucleotide Exchange Factors]
Cell biology
Fragile X syndrome
Actin Cytoskeleton
metabolism [ADP-Ribosylation Factors]
metabolism [Neurons]
Knockout mouse
RNA Interference
ultrastructure [Dendritic Spines]
Guanosine Triphosphate
metabolism [Receptors
Metabotropic Glutamate]
metabolism [Guanine Nucleotide Exchange Factors]
metabolism [Guanosine Triphosphate]
congenital
hereditary
and neonatal diseases and abnormalities
Dendritic Spines
Nerve Tissue Proteins
Biology
genetics [Fragile X Mental Retardation Protein]
03 medical and health sciences
Cellular and Molecular Neuroscience
medicine
Animals
ddc:610
metabolism [Synaptosomes]
genetics [Fragile X Syndrome]
medicine.disease
Actin cytoskeleton
FMR1
Mice
Inbred C57BL
030104 developmental biology
Metabotropic glutamate receptor
ADP-Ribosylation Factor 6
Fragile X Syndrome
Synaptic plasticity
030217 neurology & neurosurgery
Synaptosomes
Zdroj: Journal of neurochemistry 157(3), 666-683 (2021). doi:10.1111/jnc.15230
Journal of Neurochemistry : official journal of the International Society for Neurochemistry
ISSN: 1471-4159
DOI: 10.1111/jnc.15230
Popis: 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.
Databáze: OpenAIRE
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