ADP ribosylation factor 6 (ARF6) controls amyloid precursor protein (APP) processing by mediating the endosomal sorting of BACE1

Sannerud, Ragna; Declerck, Ilse; Perić, Aleksandar; Raemaekers, Tim; Menéndez, Guillermo; Zhou, Lujia; Baert, Veerle; Coen, Katrijn; Munck, Sebastian; Strooper, Bart De; Schiavo, Giampietro; Annaert, Wim

doi:10.1073/pnas.1100745108

Cited by 217 publications

(254 citation statements)

References 66 publications

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“…1C, dotted lines), and we also found colocalization in vesicular structures inside the growth cone (arrows). Expression of constitutively active ARF6-Q67L is known to cause enlarged endosomal structures containing ARF6-regulated membrane constituents (Brown et al, 2001;Aikawa and Martin, 2003;Naslavsky et al, 2003;Sannerud et al, 2011). We found that ARF6-Q67L expression generated enlarged endosomal structures that were positive for both ARF6-Q67L and ␤1 integrin throughout adult DRG neurons, including at the cell body (data not shown) and growth cone where vacuolar structures were found aggregating in the central domain (Fig.…”

Section: Does Arf6 Colocalize With Integrin In Axons and Growth Cones?mentioning

confidence: 62%

“…Future work will investigate whether there is a trafficking role for ARF6 in mature CNS axons, or whether it is mainly restricted to the somatodendritic compartment. ARF6 is involved in a number of postsynaptic functions within dendritic spines (Choi et al, 2006;Sakagami et al, 2008;Scholz et al, 2010;Fukaya et al, 2011), and is reported to be largely absent from axons of mature hippocampal neurons in culture (Sannerud et al, 2011); however, it is also reported to function presynaptically (Ashery et al, 1999; Krauss et al, 2003), which might indicate that there is a population of ARF6-positive vesicles trafficking within some adult CNS axons.…”

Section: Integrins Traffic Via Arf6 In Adult Drg Axonsmentioning

confidence: 99%

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ARF6 Directs Axon Transport and Traffic of Integrins and Regulates Axon Growth in Adult DRG Neurons

Eva¹,

Crisp²,

Marland³

et al. 2012

Journal of Neuroscience

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Integrins are involved in axon growth and regeneration. Manipulation of integrins is a route to promoting axon regeneration and understanding regeneration failure in the CNS. Expression of ␣9 integrin promotes axon regeneration, so we have investigated ␣9␤1 trafficking and transport in axons and at the growth cone. We have previously found that ␣9 and ␤1 integrins traffic via Rab11-positive recycling endosomes in peripheral axons and growth cones. However, transport via Rab11 is slow, while rapid transport occurs in vesicles lacking Rab11. We have further studied ␣9 and ␤1 integrin transport and traffic in adult rat dorsal root ganglion axons and PC12 cells. Integrins are in ARF6 vesicles during rapid axonal transport and during trafficking in the growth cone. We report that rapid axonal transport of these integrins and their trafficking at the cell surface is regulated by ARF6. ARF6 inactivation by expression of ACAP1 leads to increased recycling of ␤1 integrins to the neuronal surface and to increased anterograde axonal transport. ARF6 activation by expression of the neuronal guanine nucleotide exchange factors, ARNO or EFA6, increases retrograde integrin transport in axons and increases integrin internalization. ARF6 inactivation increases integrin-mediated outgrowth, while activation decreases it. The coordinated changes in integrin transport and recycling resulting from ARF6 activation or inactivation are the probable mechanism behind this regulation of axon growth. Our data suggest a novel mechanism of integrin traffic and transport in peripheral axons, regulated by the activation state of ARF6, and suggest that ARF6 might be targeted to enhance integrin-dependent axon regeneration after injury.

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Section: Does Arf6 Colocalize With Integrin In Axons and Growth Cones?mentioning

confidence: 62%

Section: Integrins Traffic Via Arf6 In Adult Drg Axonsmentioning

confidence: 99%

ARF6 Directs Axon Transport and Traffic of Integrins and Regulates Axon Growth in Adult DRG Neurons

Eva¹,

Crisp²,

Marland³

et al. 2012

Journal of Neuroscience

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“…Altered expression has been described previously in patients with AD, Parkinson's, and Huntington's disease [68], as well as animal models of neurodegeneration [69], however, investigation of this cell signaling molecule in the neurodegeneration field is relatively novel. As previously suggested, the changes in mRNA expression of IQSEC1 may not be biologically significant, since there was a small difference in fold change between sham and hypoperfused mice.…”

Section: Discussionmentioning

confidence: 99%

Elevated levels of plasma homocysteine, deficiencies in dietary folic acid and uracil–DNA glycosylase impair learning in a mouse model of vascular cognitive impairment

Jadavji

Farr

Lips

et al. 2015

Behavioural Brain Research

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(2015) Elevated levels of plasma homocysteine, deficiencies in dietary folic acid and uracil-DNA glycosylase impair learning in a mouse model of vascular cognitive impairment. Behavioural Brain Research, 283 . pp. 215-226. ISSN 1872-7549 Access from the University of Nottingham repository: http://eprints.nottingham.ac.uk/32983/9/UNG_FADD_20140826_manuscript_final.pdf Copyright and reuse:The Nottingham ePrints service makes this work by researchers of the University of Nottingham available open access under the following conditions. This article is made available under the Creative Commons Attribution Non-commercial No Derivatives licence and may be reused according to the conditions of the licence. For more details see: http://creativecommons.org/licenses/by-nc-nd/2.5/ A note on versions:The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the repository url above for details on accessing the published version and note that access may require a subscription.For more information, please contact eprints@nottingham.ac.uk Elevated levels of plasma homocysteine, deficiencies in dietary folic acid and uracil-DNA glycosylase impair learning in a mouse model of vascular cognitive impairment. ABSTRACTDietary deficiencies in folic acid result in elevated levels of plasma homocysteine, which has been associated with the development of dementia and other neurodegenerative disorders.Previously, we have shown that elevated levels of plasma homocysteine in mice deficient for a DNA repair enzyme, uracil-DNA glycosylase (UNG), result in neurodegeneration. The goal of this study was to evaluate how deficiencies in folic acid and UNG along with elevated levels of homocysteine affect vascular cognitive impairment, via chronic hypoperfusion in an animal model. Ung+/+ and Ung−/− mice were placed on either control (CD) or folic acid deficient (FADD) diets. Six weeks later, the mice either underwent implantation of microcoils around both common carotid arteries. Post-operatively, behavioral tests began at 3-weeks, angiography was measured after 5-weeks using MRI to assess vasculature and at completion of study plasma and brain tissue was collected for analysis. Learning impairments in the Morris water maze (MWM) were observed only in hypoperfused Ung−/− FADD mice and these mice had significantly higher plasma homocysteine concentrations. Interestingly, Ung+/+ FADD produced significant remodeling of the basilar artery and arterial vasculature. Increased expression of GFAP was observed in the dentate gyrus of Ung−/− hypoperfused and FADD sham mice. Chronic hypoperfusion resulted in increased cortical MMP-9 protein levels of FADD hypoperfused mice regardless of genotypes. These results suggest that elevated levels of homocysteine only, as a result of dietary folic acid deficiency, don't lead to memory impairments and neurobiochemical changes. Rather a combination of either chronic hypoperfusion o...

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“…11 This is in line with a recent observation of an association of the FRMD4A locus with plasma Aβ1 − 42/Aβ1 − 40, reinforcing the plausibility of the association of FRMD4A with Alzheimer's disease risk and its potential implication in a subtle control of the APP metabolism. 11,12 Thus, FRMD4A polymorphisms are a likely risk factor for Alzheimer's disease. Our data demonstrate that a homozygous null mutation of the same gene causes a severe neurological phenotype with unique dysmorphism.…”

Section: Discussionmentioning

confidence: 99%

A syndrome of congenital microcephaly, intellectual disability and dysmorphism with a homozygous mutation in FRMD4A

et al. 2014

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A consanguineous Bedouin Israeli kindred presented with a novel autosomal recessive intellectual disability syndrome of congenital microcephaly, low anterior hairline, bitemporal narrowing, low-set protruding ears, strabismus and tented thick eyebrows with sparse hair in their medial segment. Brain imaging demonstrated various degrees of agenesis of corpus callosum and hypoplasia of the vermis and cerebellum. Genome-wide linkage analysis followed by fine mapping defined a 7.67 Mb disease-associated locus (LOD score 4.99 at θ = 0 for marker D10S1653). Sequencing of the 48 genes within the locus identified a single non-synonymous homozygous duplication frameshift mutation of 13 nucleotides (c.2134_2146dup13) within the coding region of FRMD4A, that was common to all affected individuals and not found in 180 non-related Bedouin controls. Three of 50 remotely related healthy controls of the same tribe were heterozygous for the mutation. FRMD4A, member of the FERM superfamily, is involved in cell structure, transport and signaling. It regulates cell polarity by playing an important role in the activation of ARF6, mediating the interaction between Par3 and the ARF6 guanine nucleotide exchange factor. ARF6 is known to modulate cell polarity in neurons, and regulates dendritic branching in hippocampal neurons and neurite outgrowth. The FRMD4 domain that is essential for determining cell polarity through interaction with Par3 is truncated by the c.2134_2146dup13 mutation. FRMD4A polymorphisms were recently suggested to be a risk factor for Alzheimer's disease. We now show a homozygous frameshift mutation of the same gene in a severe neurologic syndrome with unique dysmorphism.

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ADP ribosylation factor 6 (ARF6) controls amyloid precursor protein (APP) processing by mediating the endosomal sorting of BACE1

Cited by 217 publications

References 66 publications

ARF6 Directs Axon Transport and Traffic of Integrins and Regulates Axon Growth in Adult DRG Neurons

ARF6 Directs Axon Transport and Traffic of Integrins and Regulates Axon Growth in Adult DRG Neurons

Elevated levels of plasma homocysteine, deficiencies in dietary folic acid and uracil–DNA glycosylase impair learning in a mouse model of vascular cognitive impairment

A syndrome of congenital microcephaly, intellectual disability and dysmorphism with a homozygous mutation in FRMD4A

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