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

Abstract

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.

Centrosomal Enrichment and Proteasomal Degradation of SYS-1/β-catenin Requires the Microtubule Motor Dynein

“…Interestingly, the rsa-2(RNAi) enhancement of kinetochore localization of SYS-1 in this model is consistent with ‘traffic jams’ observed in microtubule mediated trafficking (Leduc, Howard et al 2012). In these cases, crowding motors by increasing the local concentration of motor proteins, introducing microtubule-binding obstacles, or, importantly for our model, preventing terminal motor dissociation limits the activity of motor proteins (Nam and Epureanu, 2017; Ferro, Yildiz et al 2019). Evidence of traffic jams in vivo have been shown in neuronal microtubule transport, as neuronal kinesin and its cargo synaptotagmin accumulate when trafficking is disrupted by hypomorphic kinesin alleles.…”

Atomic Force Microscopy Applied to the Study of Tauopathies

“…However, many new physiological functions in different cellular compartments were discovered later. Regarding microtubules, tau is pivotal for the assembly and stability of their bundle, regulation of axonal transport, , and protection from cleavage . Concerning synaptic activity, tau acts on long-term potentiation and depression, , regulation of neuronal hyperexcitability, neuro- and synaptogenesis, and last but not least, learning and memory. − Besides, tau also plays a role in the myelination process, mitochondrial health, the integrity of genomic DNA and cytoplasmic and nuclear RNA, , regulation of iron transport, glucose homeostasis in neurons, control of anxiety and insomnia, and motor function .…”

“…However, many new physiological functions in different cellular compartments were discovered later. Regarding microtubules, tau is pivotal for the assembly and stability of their bundle, 22 regulation of axonal transport, 95,96 and protection from cleavage. 97 Concerning synaptic activity, tau acts on long-term potentiation and depression, 98,99 regulation of neuronal hyperexcitability, 100 neuro-and synaptogenesis, 101 and last but not least, learning and memory.…”

The Beacon Calculus: A formal method for the flexible and concise modelling of biological systems

“…The two definitions for kinesin below, K1 and K2, are equivalent. Tau is a neuronal microtubule associated protein that diffuses up and down microtubules [15] and increases the rate of kinesin unbinding [4,20]. In the following example, a tau protein diffuses on the microtubule and keeps a beacon active at its current position.…”