Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The role of stretching in slow axonal transport.

ABSTRACT: Axonal stretching is linked to rapid rates of axonal elongation. Yet the impact of stretching on elongation and slow axonal transport is unclear. Here, we develop a mathematical model of slow axonal transport that incorporates the rate of axonal elongation, protein half-life, protein density, adhesion strength, and axonal viscosity to quantify the effects of axonal stretching. We find that under conditions where the axon (or nerve) is free of a substrate and lengthens at rapid rates (>4 mm day?¹), stretching can account for almost 50% of total anterograde axonal transport. These results suggest that it is possible to accelerate elongation and transport simultaneously by increasing either the axon's susceptibility to stretching or the forces that induce stretching. To our knowledge, this work is the first to incorporate the effects of stretching in a model of slow axonal transport. It has relevance to our understanding of neurite outgrowth during development and peripheral nerve regeneration after trauma, and hence to the development of treatments for spinal cord injury.

SUBMITTER: O'Toole M

PROVIDER: S-EPMC3021655 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

The role of stretching in slow axonal transport.

O'Toole Matthew M Miller Kyle E KE

Biophysical journal 20110101 2

Axonal stretching is linked to rapid rates of axonal elongation. Yet the impact of stretching on elongation and slow axonal transport is unclear. Here, we develop a mathematical model of slow axonal transport that incorporates the rate of axonal elongation, protein half-life, protein density, adhesion strength, and axonal viscosity to quantify the effects of axonal stretching. We find that under conditions where the axon (or nerve) is free of a substrate and lengthens at rapid rates (>4 mm day⁻¹ ...[more]

PMID: 21244831

Similar Datasets

Kinesin-1/Hsc70-dependent mechanism of slow axonal transport and its relation to fast axonal transport.

Project description:Cytoplasmic protein transport in axons ('slow axonal transport') is essential for neuronal homeostasis, and involves Kinesin-1, the same motor for membranous organelle transport ('fast axonal transport'). However, both molecular mechanisms of slow axonal transport and difference in usage of Kinesin-1 between slow and fast axonal transport have been elusive. Here, we show that slow axonal transport depends on the interaction between the DnaJ-like domain of the kinesin light chain in the Kinesin-1 motor complex and Hsc70, scaffolding between cytoplasmic proteins and Kinesin-1. The domain is within the tetratricopeptide repeat, which can bind to membranous organelles, and competitive perturbation of the domain in squid giant axons disrupted cytoplasmic protein transport and reinforced membranous organelle transport, indicating that this domain might have a function as a switchover system between slow and fast transport by Hsc70. Transgenic mice overexpressing a dominant-negative form of the domain showed delayed slow transport, accelerated fast transport and optic axonopathy. These findings provide a basis for the regulatory mechanism of intracellular transport and its intriguing implication in neuronal dysfunction.

| S-EPMC2829163 | biostudies-literature

Cytoskeletal requirements in axonal transport of slow component-b.

Project description:Slow component-b (SCb) translocates approximately 200 diverse proteins from the cell body to the axon and axon tip at average rates of approximately 2-8 mm/d. Several studies suggest that SCb proteins are cotransported as one or more macromolecular complexes, but the basis for this cotransport is unknown. The identification of actin and myosin in SCb led to the proposal that actin filaments function as a scaffold for the binding of other SCb proteins and that transport of these complexes is powered by myosin: the "microfilament-complex" model. Later, several SCb proteins were also found to bind F-actin, supporting the idea, but despite this, the model has never been directly tested. Here, we test this model by disrupting the cytoskeleton in a live-cell model system wherein we directly visualize transport of SCb cargoes. We focused on three SCb proteins that we previously showed were cotransported in our system: alpha-synuclein, synapsin-I, and glyceraldehyde-3-phosphate dehydrogenase. Disruption of actin filaments with latrunculin had no effect on the velocity or frequency of transport of these three proteins. Furthermore, cotransport of these three SCb proteins continued in actin-depleted axons. We conclude that actin filaments do not function as a scaffold to organize and transport these and possibly other SCb proteins. In contrast, depletion of microtubules led to a dramatic inhibition of vectorial transport of SCb cargoes. These findings do not support the microfilament-complex model, but instead indicate that the transport of protein complexes in SCb is powered by microtubule motors.

| S-EPMC2648304 | biostudies-literature

The interplay of active and passive mechanisms in slow axonal transport.

Project description:A combination of intermittent active movement of transient aggregates and a paused state that intervenes between periods of active transport has been proposed to underlie the slow, directed transport of soluble proteins in axons. A component of passive diffusion in the axoplasm may also contribute to slow axonal transport, although quantitative estimates of the relative contributions of diffusive and active movement in the slow transport of a soluble protein, and in particular how they might vary across developmental stages, are lacking. Here, we propose and study a model for slow axonal transport, addressing data from bleach recovery measurements on a small, soluble, protein, choline acetyltransferase, in thin axons of the lateral chordotonal (lch5) sensory neurons of Drosophila. Choline acetyltransferase is mainly present in soluble form in the axon and catalyzes the acetylation of choline at the synapse. It does not form particulate structures in axons and moves at rates characteristic of slow component b (≈ 1-10 mm/day or 0.01-0.1 μm/s). Using our model, which incorporates active transport with paused and/or diffusive states, we predict bleach recovery, transport rates, and cargo trajectories obtained through kymographs, comparing these with experimental observations at different developmental stages. We show that changes in the diffusive fraction of cargo during these developmental stages dominate bleach recovery and that a combination of active motion with a paused state alone cannot reproduce the data. We compared predictions of the model with results from photoactivation experiments. The importance of the diffusive state in reproducing the bleach recovery signal in the slow axonal transport of small soluble proteins is our central result.

| S-EPMC9892612 | biostudies-literature

Processive flow by biased polymerization mediates the slow axonal transport of actin.

Project description:Classic pulse-chase studies have shown that actin is conveyed in slow axonal transport, but the mechanistic basis for this movement is unknown. Recently, we reported that axonal actin was surprisingly dynamic, with focal assembly/disassembly events ("actin hotspots") and elongating polymers along the axon shaft ("actin trails"). Using a combination of live imaging, superresolution microscopy, and modeling, in this study, we explore how these dynamic structures can lead to processive transport of actin. We found relatively more actin trails elongated anterogradely as well as an overall slow, anterogradely biased flow of actin in axon shafts. Starting with first principles of monomer/filament assembly and incorporating imaging data, we generated a quantitative model simulating axonal hotspots and trails. Our simulations predict that the axonal actin dynamics indeed lead to a slow anterogradely biased flow of the population. Collectively, the data point to a surprising scenario where local assembly and biased polymerization generate the slow axonal transport of actin without involvement of microtubules (MTs) or MT-based motors. Mechanistically distinct from polymer sliding, this might be a general strategy to convey highly dynamic cytoskeletal cargoes.

| S-EPMC6314539 | biostudies-literature

Axonal transport cargo motor count versus average transport velocity: is fast versus slow transport really single versus multiple motor transport?

Project description:Cargos have been observed exhibiting a "stop-and-go" behavior (i.e. cargo "pause"), and it has generally been assumed that these multi-second pauses can be attributed to equally long pauses of cargo-bound motors during motor procession. We contend that a careful examination of the isolated microtubule experimental record does not support motor pauses. Rather, we believe that the data suggests that motor cargo complexes encounter an obstruction that prevents procession, eventually detach and reattach, with this obstructed-detach-reattach sequence being observed in axon as a "pause." Based on this, along with our quantitative evidence-based contention that slow and fast axonal transport are actually single and multi-motor transport, we have developed a cargo level motor model capable of exhibiting the full range of slow to fast transport solely by changing the number of motors involved. This computational model derived using first-order kinetics is suitable for both kinesin and dynein and includes load-dependence as well as provision for motors encountering obstacles to procession. The model makes the following specific predictions: average distance from binding to obstruction is about 10 μm; average motor maximum velocity is at least 6 μm/s in axon; a minimum of 10 motors is required for the fastest fast transport while only one motor is required for slow transport; individual in-vivo cargo-attached motors may spend as little as 5% of their time processing along a microtubule with the remainder being spent either obstructed or unbound to a microtubule; and at least in the case of neurofilament transport, kinesin and dynein are largely not being in a "tug-of-war" competition.

| S-EPMC4359950 | biostudies-literature

Hsc70 chaperone activity is required for the cytosolic slow axonal transport of synapsin.

Project description:Soluble cytosolic proteins vital to axonal and presynaptic function are synthesized in the neuronal soma and conveyed via slow axonal transport. Our previous studies suggest that the overall slow transport of synapsin is mediated by dynamic assembly/disassembly of cargo complexes followed by short-range vectorial transit (the "dynamic recruitment" model). However, neither the composition of these complexes nor the mechanistic basis for the dynamic behavior is understood. In this study, we first examined putative cargo complexes associated with synapsin using coimmunoprecipitation and multidimensional protein identification technology mass spectrometry (MS). MS data indicate that synapsin is part of a multiprotein complex enriched in chaperones/cochaperones including Hsc70. Axonal synapsin-Hsc70 coclusters are also visualized by two-color superresolution microscopy. Inhibition of Hsc70 ATPase activity blocked the slow transport of synapsin, disrupted axonal synapsin organization, and attenuated Hsc70-synapsin associations, advocating a model where Hsc70 activity dynamically clusters cytosolic proteins into cargo complexes, allowing transport. Collectively, our study offers insight into the molecular organization of cytosolic transport complexes and identifies a novel regulator of slow transport.

| S-EPMC5496608 | biostudies-literature

A close look at axonal transport: Cargos slow down when crossing stationary organelles.

Project description:The bidirectional transport of cargos along the thin axon is fundamental for the structure, function and survival of neurons. Defective axonal transport has been linked to the mechanism of neurodegenerative diseases. In this paper, we study the effect of the local axonal environment to cargo transport behavior in neurons. Using dual-color fluorescence imaging in microfluidic neuronal devices, we quantify the transport dynamics of cargos when crossing stationary organelles such as non-moving endosomes and stationary mitochondria in the axon. We show that the axonal cargos tend to slow down, or pause transiently within the vicinity of stationary organelles. The slow-down effect is observed in both retrograde and anterograde transport directions of three different cargos (TrkA, lysosomes and TrkB). Our results agree with the hypothesis that bulky axonal structures can pose as steric hindrance for axonal transport. However, the results do not rule out the possibility that cellular mechanisms causing stationary organelles are also responsible for the delay in moving cargos at the same locations.

| S-EPMC4695265 | biostudies-literature

Quantitative analysis of APP axonal transport in neurons: role of JIP1 in enhanced APP anterograde transport.

Project description:Alzheimer's ?-amyloid precursor protein (APP) associates with kinesin-1 via JNK-interacting protein 1 (JIP1); however, the role of JIP1 in APP transport by kinesin-1 in neurons remains unclear. We performed a quantitative analysis to understand the role of JIP1 in APP axonal transport. In JIP1-deficient neurons, we find that both the fast velocity (?2.7 ?m/s) and high frequency (66%) of anterograde transport of APP cargo are impaired to a reduced velocity (?1.83 ?m/s) and a lower frequency (45%). We identified two novel elements linked to JIP1 function, located in the central region of JIP1b, that interact with the coiled-coil domain of kinesin light chain 1 (KLC1), in addition to the conventional interaction of the JIP1b 11-amino acid C-terminal (C11) region with the tetratricopeptide repeat of KLC1. High frequency of APP anterograde transport is dependent on one of the novel elements in JIP1b. Fast velocity of APP cargo transport requires the C11 domain, which is regulated by the second novel region of JIP1b. Furthermore, efficient APP axonal transport is not influenced by phosphorylation of APP at Thr-668, a site known to be phosphorylated by JNK. Our quantitative analysis indicates that enhanced fast-velocity and efficient high-frequency APP anterograde transport observed in neurons are mediated by novel roles of JIP1b.

| S-EPMC4230617 | biostudies-literature

Role of MAP1B in axonal retrograde transport of mitochondria.

Project description:The MAPs (microtubule-associated proteins) MAP1B and tau are well known for binding to microtubules and stabilizing these structures. An additional role for MAPs has emerged recently where they appear to participate in the regulation of transport of cargos on the microtubules found in axons. In this role, tau has been associated with the regulation of anterograde axonal transport. We now report that MAP1B is associated with the regulation of retrograde axonal transport of mitochondria. This finding potentially provides precise control of axonal transport by MAPs at several levels: controlling the anterograde or retrograde direction of transport depending on the type of MAP involved, controlling the speed of transport and controlling the stability of the microtubule tracks upon which transport occurs.

| S-EPMC1479764 | biostudies-other

Retrolinkin, a membrane protein, plays an important role in retrograde axonal transport.

Project description:Retrograde axonal transport plays an important role in the maintenance of neuronal functions, but the mechanism is poorly defined partly because the constituents of the retrograde transport system and their interactions have yet to be elucidated. Of special interest is how dynein/dynactin motor proteins interact with membrane cargoes. Here, we report that an endosomal vesicle protein, termed retrolinkin, functions as a receptor tethering vesicles to dynein/dynactin through BPAG1n4. Retrolinkin, a membrane protein highly enriched in neuronal endosomes, binds directly to BPAG1n4. Deletion of retrolinkin membrane-association domains disrupts retrograde vesicular transport, recapitulating the BPAG1 null phenotype. We propose that retrolinkin acts with BPAG1n4 to specifically regulate retrograde axonal transport. Our work lays the foundation for understanding fundamental issues of axonal transport and provides insights into the molecular mechanisms underlying human neurodegenerative disorders.

| S-EPMC1892971 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data