Effects of Obstacles on the Dynamics of Kinesins, Including Velocity and Run Length, Predicted by a Model of Two Dimensional Motion

Nam, Woochul; Epureanu, Bogdan I.

doi:10.1371/journal.pone.0147676

Cited by 3 publications

(10 citation statements)

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“…Several details may explain these motility dynamics. First, as the infection progresses, more and more viral particles and proteins are produced and transported in the axon, which leads to steric hindrance and affects motor movement along microtubules (47,48). Second, HSV-1 induces mitochondrial damage (49,50) and affects power supply and cell energy.…”

Section: Discussionmentioning

confidence: 99%

Anterograde Viral Tracer Herpes Simplex Virus 1 Strain H129 Transports Primarily as Capsids in Cortical Neuron Axons

Xiao

Zhou

Qin

et al. 2020

J Virol

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The features of herpes simplex virus 1 (HSV-1) strain 129 (H129), including natural neurotropism and anterograde transneuronal trafficking, make it a potential tool for anterograde neural circuitry tracing. Recently anterograde polysynaptic and monosynaptic tracers were developed from H129 and have been applied for the identification of novel connections and functions of different neural circuitries. However, how H129 viral particles are transported in neurons, especially those of the central nervous system, remains unclear. In this study, we constructed recombinant H129 variants with mCherry-labeled capsids and/or green fluorescent protein (GFP)-labeled envelopes and infected the cortical neurons to study axonal transport of H129 viral particles. We found that different types of viral particles were unevenly distributed in the nucleus, cytoplasm of the cell body, and axon. Most H129 progeny particles were unenveloped capsids and were transported as capsids rather than virions in the axon. Notably, capsids acquired envelopes at axonal varicosities and terminals where the sites forming synapses are connected with other neurons. Moreover, viral capsids moved more frequently in the anterograde direction in axons, with an average velocity of 0.62 ± 0.18 μm/s and maximal velocity of 1.80 ± 0.15 μm/s. We also provided evidence that axonal transport of capsids requires the kinesin-1 molecular motor. These findings support that H129-derived tracers map the neural circuit anterogradely and possibly transsynaptically. These data will guide future modifications and improvements of H129-based anterograde viral tracers. IMPORTANCE Anterograde transneuronal tracers derived from herpes simplex virus 1 (HSV-1) strain 129 (H129) are important tools for mapping neural circuit anatomic and functional connections. It is, therefore, critical to elucidate the transport pattern of H129 within neurons and between neurons. We constructed recombinant H129 variants with genetically encoded fluorescence-labeled capsid protein and/or glycoprotein to visualize viral particle movement in neurons. Both electron microscopy and light microscopy data show that H129 capsids and envelopes move separately, and notably, capsids are enveloped at axonal varicosity and terminals, which are the sites forming synapses to connect with other neurons. Superresolution microscopy-based colocalization analysis and inhibition of H129 particle movement by inhibitors of molecular motors support that kinesin-1 contributes to the anterograde transport of capsids. These results shed light into the mechanisms for anterograde transport of H129-derived tracer in axons and transmission between neurons via synapses, explaining the anterograde labeling of neural circuits by H129-derived tracers.

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Section: Discussionmentioning

confidence: 99%

Anterograde Viral Tracer Herpes Simplex Virus 1 Strain H129 Transports Primarily as Capsids in Cortical Neuron Axons

Xiao

Zhou

Qin

et al. 2020

J Virol

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“…For kinesins bound to MTs, the walking motion, the unbinding, and the interaction between cargoes and kinesins are captured with previously developed mechanistic models [23][24][25][26]. The walking motion of kinesin is determined by the period and direction of its step [5,27].…”

Section: A Kinesin Bound To a Mt: Walking And Unbindingmentioning

confidence: 99%

“…While a kinesin takes a step, one of its heads is bound to the MT and the other head moves by diffusion and a conformational change in its structure. The direction of a step is considered according to the previously developed model [26] which is capable of capturing the diffusing motion of the kinesin head. Kinesin heads are connected to neck linkers, as shown in Figure 1 (a).…”

Section: A Kinesin Bound To a Mt: Walking And Unbindingmentioning

confidence: 99%

“…A nonlinear stiffness of the neck linker was also considered when capturing the diffusing motion of the head. The unbinding probability calculated in previous studies [25,26] is used to capture the stochastic instant of release from the MT. When a kinesin walks along a MT, the motion of its cargo is calculated with…”

Section: A Kinesin Bound To a Mt: Walking And Unbindingmentioning

confidence: 99%

“…r c is the radius of the cargo, and η is the viscosity of the fluid in the axon. Details on walking and unbinding are provided in our previous works [23][24][25][26].…”

Section: A Kinesin Bound To a Mt: Walking And Unbindingmentioning

confidence: 99%

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Dynamic model for kinesin-mediated long-range transport and its local traffic jam caused by tau proteins

Nam

Epureanu

2017

Phys. Rev. E

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In neurons, several intracellular cargoes are transported by motor proteins (kinesins) which walk on microtubules (MTs). However, kinesins can possibly unbind from the MTs before they reach their destinations. The unbound kinesins randomly diffuse in neurons until they bind to MTs. Then, they walk again along the MTs to continue their tasks. Kinesins repeat this cycle of motion until they transport their cargoes to the destinations. However, most previous models mainly focused on the motion of kinesins when they walk on MTs. Thus, a new model is required to encompass the various types of kinesin motion. We developed a comprehensive model and studied the long-range axonal transport of neurons using the model. To enhance reliability of the model, it was constructed based on multiphysics on kinesin motion (i.e., chemical kinetics, diffusion, fluid dynamics, nonlinear dynamics, and stochastic characteristics). Also, parameter values for kinesin motions are carefully obtained by comparing the model predictions and several experimental observations. The axonal transport can be degraded when a large number of binding sites on MTs are blocked by excessive tau proteins. By considering the interference between walking kinesins and tau molecules on MTs, effects of tau proteins on the axonal transport are studied. One of the meaningful predictions obtained from the model is that the velocity is not an effective metric to estimate the degradation of the transport because the decrease in velocity is not noticeable when the concentration of tau protein is not high. However, our model shows that the transport locally changes near tau molecules on MTs even when the change in the velocity is not significant. Thus, a statistical method is proposed to detect this local change effectively. The advantage of this method is that a value obtained from this method is highly sensitive to the concentration of tau protein. Another benefit of this method is that this highly sensitive value can be acquired with relatively low precision and low temporal resolution considering the time scale and length scale of the kinesin motion. This method can be used to estimate the condition of the axonal transport system.

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Theoretical perspectives on biological machines

et al. 2020

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Many biological functions are executed by molecular machines, which like man made motors consume energy and convert it into mechanical work. Biological machines have evolved to transport cargo, facilitate folding of proteins and RNA, remodel chromatin and replicate DNA. A common aspect of these machines is that their functions are driven by fuel provided by hydrolysis of ATP or GTP, thus driving them out of equilibrium. It is a challenge to provide a general framework for understanding the functions of biological machines, such as molecular motors (kinesin, dynein, and myosin), molecular chaperones, and helicases. Using these machines, whose structures have little resemblance to one another, as prototypical examples, we describe a few general theoretical methods that have provided insights into their functions. Although the theories rely on coarse-graining of these complex systems they have proven useful in not only accounting for many in vitro experiments but also address questions such as how the trade-off between precision, energetic costs and optimal performances are balanced. However, many complexities associated with biological machines will require one to go beyond current theoretical methods. We point out that simple point mutations in the enzyme could drastically alter functions, making the motors bi-directional or result in unexpected diseases or dramatically restrict the capacity of molecular chaperones to help proteins fold. These examples are reminders that while the search for principles of generality in biology is intellectually stimulating, one also ought to keep in mind that molecular details must be accounted for to develop a deeper understanding of processes driven by biological machines. Going beyond generic descriptions of in vitro behavior to making genuine understanding of in vivo functions will likely remain a major challenge for some time to come. In this context, the combination of careful experiments and the use of physics and physical chemistry principles will be useful in elucidating the rules governing the workings of biological machines.

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Effects of Obstacles on the Dynamics of Kinesins, Including Velocity and Run Length, Predicted by a Model of Two Dimensional Motion

Cited by 3 publications

References 55 publications

Anterograde Viral Tracer Herpes Simplex Virus 1 Strain H129 Transports Primarily as Capsids in Cortical Neuron Axons

Anterograde Viral Tracer Herpes Simplex Virus 1 Strain H129 Transports Primarily as Capsids in Cortical Neuron Axons

Dynamic model for kinesin-mediated long-range transport and its local traffic jam caused by tau proteins

Theoretical perspectives on biological machines

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