APache Is an AP2-Interacting Protein Involved in Synaptic Vesicle Trafficking and Neuronal Development

Piccini, Alessandra; Castroflorio, Enrico; Valente, Pierluigi; Guarnieri, Fabrizia C.; Aprile, Davide; Michetti, Caterina; Bramini, Mattia; Giansante, Giorgia; Pinto, Bruno; Savardi, Annalisa; Cesca, Fabrizia; Bachi, Ángela; Cattaneo, Angela; Wren, Jonathan D.; Valtorta, Flavia; Benfenati, Fabio; Giovedì, Silvia

doi:10.1016/j.celrep.2017.11.073

Cited by 15 publications

(9 citation statements)

References 53 publications

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“…DAVID analysis ( Dennis et al, 2003 ) of the proteome found a significant enrichment for the biological processes of ‘synaptic vesicle endocytosis’ (22 proteins, p=1.7x10 −6 ) and ‘synaptic vesicle exocytosis’ (30 proteins, p=3.6x10 −9 ), among others. Eight proteins were of unknown function, not including the previously uncharacterized Kiaa1107 (APache) which was recently shown to be involved in synaptic vesicle trafficking ( Piccini et al, 2017 ). The only protein in the network strongly associated with the postsynaptic density (PSD) was Shank1, but there is recent evidence that Shank proteins have an unappreciated presynaptic function ( Wu et al, 2017 ).…”

Section: Resultsmentioning

confidence: 99%

Action potential-coupled Rho GTPase signaling drives presynaptic plasticity

O'Neil

Rácz

Brown

et al. 2021

eLife

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In contrast to their postsynaptic counterparts, the contributions of activity-dependent cytoskeletal signaling to presynaptic plasticity remain controversial and poorly understood. To identify and evaluate these signaling pathways, we conducted a proteomic analysis of the presynaptic cytomatrix using in vivo biotin identification (iBioID). The resultant proteome was heavily enriched for actin cytoskeleton regulators, including Rac1, a Rho GTPase that activates the Arp2/3 complex to nucleate branched actin filaments. Strikingly, we find Rac1 and Arp2/3 are closely associated with synaptic vesicle membranes in adult mice. Using three independent approaches to alter presynaptic Rac1 activity (genetic knockout, spatially restricted inhibition, and temporal optogenetic manipulation), we discover that this pathway negatively regulates synaptic vesicle replenishment at both excitatory and inhibitory synapses, bidirectionally sculpting short-term synaptic depression. Finally, we use two-photon fluorescence lifetime imaging to show that presynaptic Rac1 activation is coupled to action potentials by voltage-gated calcium influx. Thus, this study uncovers a previously unrecognized mechanism of actin-regulated short-term presynaptic plasticity that is conserved across excitatory and inhibitory terminals. It also provides a new proteomic framework for better understanding presynaptic physiology, along with a blueprint of experimental strategies to isolate the presynaptic effects of ubiquitously expressed proteins.

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Section: Resultsmentioning

confidence: 99%

Action potential-coupled Rho GTPase signaling drives presynaptic plasticity

O'Neil

Rácz

Brown

et al. 2021

eLife

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“…GAD2 encodes an enzyme that catalyzes the decarboxylation of glutamate to GABA and CO 2 55 . Interestingly, SYT1 , an integral membrane protein involved in synaptic vesicles, co-localizes with KIAA1107 , the gene differentially expressed in stem cell models and brains from MAPT p.R406W carriers and PSP brains, in neurons 56 .…”

Section: Discussionmentioning

confidence: 99%

Integrative system biology analyses of CRISPR-edited iPSC-derived neurons and human brains reveal deficiencies of presynaptic signaling in FTLD and PSP

Jiang

Wen

et al. 2018

Transl Psychiatry

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Mutations in the microtubule-associated protein tau (MAPT) gene cause autosomal dominant frontotemporal lobar degeneration with tau inclusions (FTLD-tau). MAPT p.R406W carriers present clinically with progressive memory loss and neuropathologically with neuronal and glial tauopathy. However, the pathogenic events triggered by the expression of the mutant tau protein remain poorly understood. To identify the genes and pathways that are dysregulated in FTLD-tau, we performed transcriptomic analyses in induced pluripotent stem cell (iPSC)–derived neurons carrying MAPT p.R406W and CRISPR/Cas9-corrected isogenic controls. We found that the expression of the MAPT p.R406W mutation was sufficient to create a significantly different transcriptomic profile compared with that of the isogeneic controls and to cause the differential expression of 328 genes. Sixty-one of these genes were also differentially expressed in the same direction between MAPT p.R406W carriers and pathology-free human control brains. We found that genes differentially expressed in the stem cell models and human brains were enriched for pathways involving gamma-aminobutyric acid (GABA) receptors and pre-synaptic function. The expression of GABA receptor genes, including GABRB2 and GABRG2, were consistently reduced in iPSC-derived neurons and brains from MAPT p.R406W carriers. Interestingly, we found that GABA receptor genes, including GABRB2 and GABRG2, are significantly lower in symptomatic mouse models of tauopathy, as well as in brains with progressive supranuclear palsy. Genome wide association analyses reveal that common variants within GABRB2 are associated with increased risk for frontotemporal dementia (P < 1 × 10−3). Thus, our systems biology approach, which leverages molecular data from stem cells, animal models, and human brain tissue can reveal novel disease mechanisms. Here, we demonstrate that MAPT p.R406W is sufficient to induce changes in GABA-mediated signaling and synaptic function, which may contribute to the pathogenesis of FTLD-tau and other primary tauopathies.

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“…In the SV cycle, Rab proteins involved in these processes include Rab5, Rab4, Rab11 and Rab7 (Dey et al, 2017; Inoshita et al, 2017; Pavlos and Jahn, 2011). The increase in the formation of multivesicular body-like structures in the synaptic bouton, together with the accumulation of SV and lysosomal markers in the distal axons reported by De Gregorio et al (2017), suggests that Atl knock-down is related to alterations in membrane trafficking, implying possible changes in the organization and life cycle of the SV (Piccini et al, 2017). Here we determined that Atl knock-down modifies the accumulation of SV in the endosomal compartments positive for Rab11, but not for Rab4 (early recycling endosome) or Rab7 (late endosome) (Figure 4).…”

Section: Discussionmentioning

confidence: 99%

Drosophila Atlastin regulates synaptic vesicle mobilization independent of Bone Morphogenetic Protein signaling

Bertin

Jara-Wilde

Auer

et al. 2022

Preprint

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Motor neurons are highly dependent on membrane trafficking, in which the endoplasmic reticulum (ER) and its contact sites with endosomes, confer the ER the role of a long-distance communicator. Atlastin (Atl), a large GTPase located on the ER membrane is required for its function and its tubular structural dynamics. Atl also downregulates, by a yet unknown mechanism, the BMP (Bone Morphogenic Protein) pathway. In humans, Atl mutations are the second more common cause of Hereditary Spastic Paraplegia (HSP), a genetic disease characterized by spasticity of the lower extremities. Here, we explore the molecular basis of Atl-dependent defects on synaptic vesicle (SV) traffic in Drosophila under the hypothesis that those defects are the direct consequence of the Atlastin knock-down and not of the Atl-dependent BMP signaling upregulation. Motor neuronal knockdown of Atl (Atl-KD) leads to an increase in synaptic and satellite bouton number similar to an increase in BMP signaling activity (TKV-CA). Neuronal Atl-KD also associates to a reduction in the boutons of the abundance of the SV markers CSP (Cysteine string protein) and VGLUT (vesicular glutamate transporter) as well as in TKV-CA larvae, both phenotypes are suppressed by decreasing the function of BMP receptor wishful thinking expressing one copy of the mutant receptor (wit /+). Surprisingly, we determined in Atl-KD larvae an increase in the CSP peripheral density and distribution, dependent on synaptic stimulation, that was not replicated in Tkv-CA larvae, suggesting that there could be differences in the mechanisms that underlie the reduction in CSP abundance. Additionally, we determined that Atl-KD associates to an increase in FM 1-43 unload but not in TKV-CA larvae. Moreover, one copy of wit was not able to suppress the FM-143 in Atl-KD larvae (Atl-KD, wit), supporting that BMP signaling does not participate in this phenotype. Together with the stimuli-dependent changes in the SV distribution and dynamics determined in Atl-KD larvae, we measured an increase in Rab11/CSP colocalization, suggesting changes in SV traffic through late recycling endosomes. Together our results suggest a mechanism by which the loss of an ER structuring protein in the motor neuron could, through its role in regulating SV and endosomal trafficking, explain defects in SV accumulation and synaptic dysfunction.

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APache Is an AP2-Interacting Protein Involved in Synaptic Vesicle Trafficking and Neuronal Development

Cited by 15 publications

References 53 publications

Action potential-coupled Rho GTPase signaling drives presynaptic plasticity

Action potential-coupled Rho GTPase signaling drives presynaptic plasticity

Integrative system biology analyses of CRISPR-edited iPSC-derived neurons and human brains reveal deficiencies of presynaptic signaling in FTLD and PSP

Drosophila Atlastin regulates synaptic vesicle mobilization independent of Bone Morphogenetic Protein signaling

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