Activity-dependent bulk endocytosis proteome reveals a key presynaptic role for the monomeric GTPase Rab11

Kokotos, Alexandros C.; Peltier, Julien; Davenport, Elizabeth C.; Trost, Matthias; Cousin, Michael A.

doi:10.1073/pnas.1809189115

Cited by 49 publications

(59 citation statements)

References 87 publications

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“…Calcineurin is located on bulk endosomes (Kokotos et al ) and plays a key role in SV generation from these organelles (Cheung and Cousin ). We showed that SV generation was disrupted when a competitive peptide that interferes with calcineurin interactions was applied to neurons, indicating that calcineurin must be located closely to sites of calcium efflux on bulk endosomes.…”

Section: Discussionmentioning

confidence: 99%

Synaptic vesicle generation from activity‐dependent bulk endosomes requires a dephosphorylation‐dependent dynamin–syndapin interaction

Cheung

Cousin

2019

Journal of Neurochemistry

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Activity‐dependent bulk endocytosis generates synaptic vesicles (SVs) during intense neuronal activity via a two‐step process. First, bulk endosomes are formed direct from the plasma membrane from which SVs are then generated. SV generation from bulk endosomes requires the efflux of previously accumulated calcium and activation of the protein phosphatase calcineurin. However, it is still unknown how calcineurin mediates SV generation. We addressed this question using a series of acute interventions that decoupled the generation of SVs from bulk endosomes in rat primary neuronal culture. This was achieved by either disruption of protein–protein interactions via delivery of competitive peptides, or inhibition of enzyme activity by known inhibitors. SV generation was monitored using either a morphological horseradish peroxidase assay or an optical assay that monitors the replenishment of the reserve SV pool. We found that SV generation was inhibited by, (i) peptides that disrupt calcineurin interactions, (ii) an inhibitor of dynamin I GTPase activity and (iii) peptides that disrupt the phosphorylation‐dependent dynamin I–syndapin I interaction. Peptides that disrupted syndapin I interactions with eps15 homology domain‐containing proteins had no effect. This revealed that (i) calcineurin must be localized at bulk endosomes to mediate its effect, (ii) dynamin I GTPase activity is essential for SV fission and (iii) the calcineurin‐dependent interaction between dynamin I and syndapin I is essential for SV generation. We therefore propose that a calcineurin‐dependent dephosphorylation cascade that requires both dynamin I GTPase and syndapin I lipid‐deforming activity is essential for SV generation from bulk endosomes.

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Section: Discussionmentioning

confidence: 99%

Synaptic vesicle generation from activity‐dependent bulk endosomes requires a dephosphorylation‐dependent dynamin–syndapin interaction

Cheung

Cousin

2019

Journal of Neurochemistry

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“…However, ADBE inhibition results in a reduced capacity to sustain neurotransmitter release in the longer term (Nicholson-Fish et al, 2015). When one considers the scope for its bidirectional modulation (Smillie et al, 2013;Kokotos et al, 2018), this suggests that ADBE provides a plastic, scalable mechanism to alter neuronal output.…”

Section: Activity-dependent Bulk Endocytosismentioning

confidence: 99%

“…Typical SV proteins (cargoes) such as VAMP2, synaptophysin, and vesicular glutamate transporter (v-Glut) are retrieved by ADBE (Nicholson-Fish et al, 2015;Kokotos et al, 2018), though it is unclear whether this retrieval is direct or due to escape of excess cargo from saturated clustering mechanisms at the periactive zone. Some cargoes, such as VAMP4, are preferentially accumulated by ADBE, perhaps explaining why VAMP4 is also essential for this mode of endocytosis (Nicholson-Fish et al, 2015).…”

Section: Activity-dependent Bulk Endocytosismentioning

confidence: 99%

The Synaptic Vesicle Cycle Revisited: New Insights into the Modes and Mechanisms

et al. 2019

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Neurotransmission is sustained by endocytosis and refilling of synaptic vesicles (SVs) locally within the presynapse. Until recently, a consensus formed that after exocytosis, SVs are recovered by either fusion pore closure (kiss-and-run) or clathrin-mediated endocytosis directly from the plasma membrane. However, recent data have revealed that SV formation is more complex than previously envisaged. For example, two additional recycling pathways have been discovered, ultrafast endocytosis and activity-dependent bulk endocytosis, in which SVs are regenerated from the internalized membrane and synaptic endosomes. Furthermore, these diverse modes of endocytosis appear to influence both the molecular composition and subsequent physiological role of individual SVs. In addition, previously unknown complexity in SV refilling and reclustering has been revealed. This review presents a modern view of the SV life cycle and discusses how neuronal subtype, physiological temperature, and individual activity patterns can recruit different endocytic modes to generate new SVs and sculpt subsequent presynaptic performance.

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“…Indeed, VAMP4 -present in CTX-M3 -is an essential molecule for activity-dependent bulk endocytosis (ADBE), 165 and several module proteins (including RAB GTPases RAB7a and RAB18) overlap with the ADBE proteome. 166 This suggests a parsimonious explanation that this module concerns the maintenance of organelles and proteins required for long-term neuronal activity, (i.e., mitostasis and ADBE proteostasis), through activity-dependent mRNA transcription and neuropil targeting. 167 CTX-M3 does show suggestive evidence of preservation outside of cortical regions (figure S6), and it may appear cortex-specific simply because it is easier to uncover neuronal biology in regions with the highest proportion of neurons, such as the cortex.…”

Section: Discussionmentioning

confidence: 99%

The architecture of brain co-expression reveals the brain-wide basis of disease susceptibility

Hartl¹,

Ramaswami²,

Pembroke³

et al. 2020

Preprint

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Gene networks have proven their utility for elucidating transcriptome structure in the brain, yielding numerous biological insights. Most analyses have focused on expression relationships within a circumspect number of regions -how these relationships vary across a broad array of brain regions is largely unknown. By leveraging RNAsequencing in 864 samples representing 12 brain regions in a cohort of 131 phenotypically normal individuals, we identify 12 brain-wide, 114 region-specific, and 50 cross-regional co-expression modules. We replicate the majority (81%) of modules in regional microarray datasets. Nearly 40% of expressed genes fall into brain-wide modules corresponding to major cell classes and conserved biological processes.Region-specific modules comprise 25% of expressed genes and correspond to regionspecific cell types and processes, such as oxytocin signaling in the hypothalamus, or addiction pathways in the nucleus accumbens. We further leverage these modules to capture cell-type-specific lncRNA and gene isoforms, both of which contribute substantially to regional synaptic diversity. We identify enrichment of neuropsychiatric disease risk variants in brain wide and multi-regional modules, consistent with their broad impact on cell classes, and highlight specific roles in neuronal proliferation and activity-dependent processes. Finally, we examine the manner in which gene coexpression and gene regulatory networks reflect genetic risk, including the recently framed omnigenic model of disease architecture.Using this hierarchy, we form a tree of consensus co-expression networks for each split, thereby generating co-expression modules for 20 hierarchical expression categories: 12 brain region specific categories (corresponding to each sampled region), 7 multiregional categories (corresponding to multiple, structurally-linked regions, figure 1b), and a brain-wide category. The majority of the resulting modules are highly overlapping, therefore we group these modules hierarchically into groups of highly similar modules which we term "module sets" (Methods). In total, we identify 311 modules at all levels, of which 173/199 (87%) of the tissue-level modules are replicated with strong support in at least one other independent dataset (figure 1c; Methods). Finally, by using network preservation statistics on all samples within regions and meta regions, we verify that module sets are supported by strong evidence within their own regions and little evidence outside of them (figure 1d).To test whether co-expression modules vary substantially by the method used for co-expression network construction, we build modules at the tissue level using three alternative approaches: ARACNe, 34 PAM-guided graphical LASSO, 35 and Fisher-von-Mises mixture modeling. 36 We find that all methods show high pairwise clustering coefficients (figure S1e), and differ predominantly by module splitting (figure 1e). For instance, most of the differences between ARACNe clusters and WGCNA clusters come from large ARACNe modules represented as...

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Activity-dependent bulk endocytosis proteome reveals a key presynaptic role for the monomeric GTPase Rab11

Cited by 49 publications

References 87 publications

Synaptic vesicle generation from activity‐dependent bulk endosomes requires a dephosphorylation‐dependent dynamin–syndapin interaction

Synaptic vesicle generation from activity‐dependent bulk endosomes requires a dephosphorylation‐dependent dynamin–syndapin interaction

The Synaptic Vesicle Cycle Revisited: New Insights into the Modes and Mechanisms

The architecture of brain co-expression reveals the brain-wide basis of disease susceptibility

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