scholarly journals The model of local axon homeostasis - explaining the role and regulation of microtubule bundles in axon maintenance and pathology

2019 ◽  
Author(s):  
Ines Hahn ◽  
André Voelzmann ◽  
Yu-Ting Liew ◽  
Beatriz Costa-Gomes ◽  
Andreas Prokop
Keyword(s):  
Axonal Transport ◽  
Regulatory Networks ◽  
Motor Proteins ◽  
Published Data ◽  
Knowledge Gap ◽  
Cargo Transport ◽  
Physical Forces

AbstractAxons are the slender, cable-like, up to meter-long projections of neurons that electrically wire our brain and body. In spite of their challenging morphology, they usually need to be maintained for an organism’s lifetime. This makes them key lesion sites in pathological processes of ageing, injury and neurodegeneration. The morphology and physiology of axons crucially depends on the parallel bundles of microtubules (MTs), running all along to form their structural backbones and highways for life-sustaining cargo transport and organelle dynamics. Understanding how these bundles are formed and then maintained will provide important explanations for axon biology and pathology. Currently, much is known about MTs and the proteins that bind and regulate them, but very little about how they functionally integrate to regulate axons. As an attempt to bridge this important knowledge gap, we explain here the model of local axon homeostasis, based on our own experiments and published data. (1) As the default, we observe that axonal MTs have a strong bias to become disorganised, likely caused by the physical forces imposed by motor proteins and their life-sustaining functions during intra-axonal transport and dynamics. (2) Preventing MT disorganisation and promoting their bundled conformation, requires complex machinery involving most or even all major classes of MT-binding and - regulating proteins. As will be discussed, this model offers new explanations for axonopathies, in particular those linking to MT-regulating proteins and motors; it will hopefully motivate more researchers to study MTs, and help to decipher the complex regulatory networks that can explain axon biology and pathology.

scholarly journals The model of local axon homeostasis - explaining the role and regulation of microtubule bundles in axon maintenance and pathology

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Ines Hahn ◽  
André Voelzmann ◽  
Yu-Ting Liew ◽  
Beatriz Costa-Gomes ◽  
Andreas Prokop
Keyword(s):  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Motor Protein ◽  
Published Data ◽  
C Elegans ◽  
Cargo Transport ◽  
Loss Of Balance ◽  
Physical Forces

Abstract Axons are the slender, cable-like, up to meter-long projections of neurons that electrically wire our brains and bodies. In spite of their challenging morphology, they usually need to be maintained for an organism's lifetime. This makes them key lesion sites in pathological processes of ageing, injury and neurodegeneration. The morphology and physiology of axons crucially depends on the parallel bundles of microtubules (MTs), running all along to serve as their structural backbones and highways for life-sustaining cargo transport and organelle dynamics. Understanding how these bundles are formed and then maintained will provide important explanations for axon biology and pathology. Currently, much is known about MTs and the proteins that bind and regulate them, but very little about how these factors functionally integrate to regulate axon biology. As an attempt to bridge between molecular mechanisms and their cellular relevance, we explain here the model of local axon homeostasis, based on our own experiments in Drosophila and published data primarily from vertebrates/mammals as well as C. elegans. The model proposes that (1) the physical forces imposed by motor protein-driven transport and dynamics in the confined axonal space, are a life-sustaining necessity, but pose a strong bias for MT bundles to become disorganised. (2) To counterbalance this risk, MT-binding and -regulating proteins of different classes work together to maintain and protect MT bundles as necessary transport highways. Loss of balance between these two fundamental processes can explain the development of axonopathies, in particular those linking to MT-regulating proteins, motors and transport defects. With this perspective in mind, we hope that more researchers incorporate MTs into their work, thus enhancing our chances of deciphering the complex regulatory networks that underpin axon biology and pathology.

scholarly journals The Carboxyl Terminus of Tegument Protein pUL21 Contributes to Pseudorabies Virus Neuroinvasion

2019 ◽  
Vol 93 (7) ◽  
Author(s):  
Kai Yan ◽  
Jie Liu ◽  
Xiang Guan ◽  
Yi-Xin Yin ◽  
Hui Peng ◽  
...  
Keyword(s):  
Axonal Transport ◽  
Pseudorabies Virus ◽  
Motor Proteins ◽  
Retrograde Transport ◽  
Cytoplasmic Dynein ◽  
Bimolecular Fluorescence Complementation ◽  
Tegument Protein ◽  
Carboxyl Terminus ◽  
Anterograde Axonal Transport

ABSTRACTFollowing its entry into cells, pseudorabies virus (PRV) utilizes microtubules to deliver its nucleocapsid to the nucleus. Previous studies have shown that PRV VP1/2 is an effector of dynein-mediated capsid transport. However, the mechanism of PRV for recruiting microtubule motor proteins for successful neuroinvasion and neurovirulence is not well understood. Here, we provide evidence that PRV pUL21 is an inner tegument protein. We tested its interaction with the cytoplasmic light chains using a bimolecular fluorescence complementation (BiFC) assay and observed that PRV pUL21 interacts with Roadblock-1. This interaction was confirmed by coimmunoprecipitation (co-IP) assays. We also determined the efficiency of retrograde and anterograde axonal transport of PRV strains in explanted neurons using a microfluidic chamber system and investigated pUL21’s contribution to PRV neuroinvasionin vivo. Further data showed that the carboxyl terminus of pUL21 is essential for its interaction with Roadblock-1, and this domain contributes to PRV retrograde axonal transportin vitroandin vivo. Our findings suggest that the carboxyl terminus of pUL21 contributes to PRV neuroinvasion.IMPORTANCEHerpesviruses are a group of DNA viruses that infect both humans and animals. Alphaherpesviruses are distinguished by their ability to establish latent infection in peripheral neurons. After entering neurons, the herpesvirus capsid interacts with cellular motor proteins and undergoes retrograde transport on axon microtubules. This elaborate process is vital to the herpesvirus lifecycle, but the underlying mechanism remains poorly understood. Here, we determined that pUL21 is an inner tegument protein of pseudorabies virus (PRV) and that it interacts with the cytoplasmic dynein light chain Roadblock-1. We also observed that pUL21 promotes retrograde transport of PRV in neuronal cells. Furthermore, our findings confirm that pUL21 contributes to PRV neuroinvasionin vivo. Importantly, the carboxyl terminus of pUL21 is responsible for interaction with Roadblock-1, and this domain contributes to PRV neuroinvasion. This study offers fresh insights into alphaherpesvirus neuroinvasion and the interaction between virus and host during PRV infection.

KINESIN BYPASSING BLOCKAGES ON MICROTUBULE RAILS

2009 ◽  
Vol 04 (01n02) ◽  
pp. 139-151 ◽  
Author(s):  
KERSTIN DREBLOW ◽  
NIKOLINA KALCHISHKOVA ◽  
KONRAD J. BÖHM
Keyword(s):  
Axonal Transport ◽  
Motor Neurons ◽  
Experimental Approach ◽  
Mechanical Energy ◽  
Fast Axonal Transport ◽  
Effective Mechanism ◽  
Tubulin Dimer ◽  
Cargo Transport ◽  
Kinesin Molecule ◽  
Conventional Kinesin

Kinesins are motor proteins which convert the chemical energy of ATP into mechanical energy to move along proteinaceous microtubule rails and to transport different cargoes to defined intracellular destinations. It is well documented that following the track of a single protofilament is the thermodynamically most effective mechanism of kinesin movement along microtubules. However, the question arises what happens when a kinesin molecule encounters a hindrance along the protofilament. The present study describes a simple, cell-free approach which enables to study the effects of structural blockages on kinesin-based transport. This experimental approach uses dimeric conventional kinesin moving nanometre-sized gold beads along immobilized microtubules whose surface has been irreversibly decorated by blocking proteins. We demonstrated that the continuous bead transport temporarily stopped at sites of blockages, but usually continued after a certain resting time. Our results suggest that single dimeric kinesin molecules are able to change to another protofilament if the next tubulin dimer where the second head should bind is blocked. A bypassing mechanism is discussed which is considered to be one fundamental prerequisite to realize a kinesin-mediated cargo-transport along microtubules over long distances, required for e.g., the fast axonal transport in motor neurons.

scholarly journals Effects of the dynein inhibitor dynarrestin on the number of motor proteins transporting synaptic cargos

2020 ◽  
Author(s):  
Kumiko Hayashi ◽  
Miki G. Miyamoto ◽  
Shinsuke Niwa
Keyword(s):  
Axonal Transport ◽  
Optical Tweezers ◽  
Hippocampal Neurons ◽  
Motor Proteins ◽  
Force Measurement ◽  
Retrograde Transport ◽  
Long Distance ◽  
Anterograde Transport ◽  
Non Invasive ◽  
Physical Measurements

AbstractSynaptic cargo transport by kinesin and dynein in hippocampal neurons was investigated using non-invasive measurements of transport force based on non-equilibrium statistical mechanics. Although direct physical measurements such as force measurement using optical tweezers are difficult in an intracellular environment, the non-invasive estimations enabled enumerating force producing units (FPUs) carrying a cargo comprising the motor proteins generating force. The number of FPUs served as a barometer for stable and long-distance transport by multiple motors, which was then used to quantify the extent of damage to axonal transport by dynarrestin, a dynein inhibitor. We found that dynarrestin decreased the FPU for retrograde transport more than anterograde transport. In the future, these measurements may be used to quantify the damage to axonal transport resulting from neuronal diseases including Alzheimer’s, Parkinson’s, and Huntington’s diseases.

scholarly journals The presenilin loop region is essential for glycogen synthase kinase 3 β (GSK3β) mediated functions on motor proteins during axonal transport

2018 ◽  
Vol 27 (17) ◽  
pp. 2986-3001 ◽  
Author(s):  
Rupkatha Banerjee ◽  
Zoe Rudloff ◽  
Crystal Naylor ◽  
Michael C Yu ◽  
Shermali Gunawardena
Keyword(s):  
Axonal Transport ◽  
Motor Proteins ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Loop Region

scholarly journals Cargo crowding, stationary clusters and dynamical reservoirs in axonal transport

2021 ◽  
Author(s):  
Vinod Kumar ◽  
Amruta Vasudevan ◽  
Keertana Venkatesh ◽  
Reshma Maiya ◽  
Parul Sood ◽  
...  
Keyword(s):  
Axonal Transport ◽  
Molecular Motors ◽  
Experimental System ◽  
C Elegans ◽  
On Demand ◽  
Motion State ◽  
State Switching ◽  
Cargo Transport ◽  
Functional Relevance

AbstractMolecular motors drive the directed transport of presynaptic vesicles along the narrow axons of nerve cells. Stationary clusters of such vesicles are a prominent feature of axonal transport, but little is known about their physiological and functional relevance. Here, we develop a simulation model describing key features of axonal cargo transport with a view to addressing this question, benchmarking the model against our experiments in the touch neurons of C. elegans. Our simulations provide for multiple microtubule tracks and varied cargo motion states while also incorporating cargo-cargo interactions. Our model also incorporates obstacles to vesicle transport in the form of microtubule ends, stalled vesicles, and stationary mitochondria. We devise computational methodologies to simulate both axonal bleaching and axotomy, showing that our results reproduce the properties of both moving as well as stationary cargo in vivo. Increasing vesicle numbers leads to larger and more long-lived stationary clusters of vesicular cargo. Vesicle clusters are dynamically stable, explaining why they are ubiquitously seen. Modulating the rates of cargo motion-state switching allows cluster lifetimes and flux to be tuned both in simulations and experiments. We demonstrate, both in simulations and in an experimental system, that suppressing reversals leads to larger stationary vesicle clusters being formed while also reducing flux. Our simulation results support the view that the physiological significance of clusters is located in their role as dynamic reservoirs of cargo vesicles, capable of being released or sequestered on demand.

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