scholarly journals The Slow Axonal Transport of the Microtubule-Associated Protein Tau and the Transport Rates of Different Isoforms and Mutants in Cultured Neurons

2002 ◽  
Vol 22 (15) ◽  
pp. 6394-6400 ◽  
Author(s):  
Michelle A. Utton ◽  
James Connell ◽  
Ayodeji A. Asuni ◽  
Marjon van Slegtenhorst ◽  
Michael Hutton ◽  
...  
Keyword(s):  
Axonal Transport ◽  
Cultured Neurons ◽  
Slow Axonal Transport ◽  
Protein Tau ◽  
Microtubule Associated Protein Tau

Slow axonal transport of the microtubule-associated protein tau

2000 ◽  
Vol 21 ◽  
pp. 113
Author(s):  
Michelle A. Utton ◽  
Richard Killick ◽  
Andrew Grierson ◽  
Steve Ackerly ◽  
Simon Lovestone ◽  
...  
Keyword(s):  
Axonal Transport ◽  
Slow Axonal Transport ◽  
Protein Tau ◽  
Microtubule Associated Protein Tau

scholarly journals The Microtubule Associated Protein Tau Regulates KIF1A Pausing Behavior and Motility

2021 ◽  
Author(s):  
Christopher L. Berger ◽  
Dominique V. Lessard
Keyword(s):  
Neurodegenerative Diseases ◽  
Axonal Transport ◽  
Single Molecule ◽  
Long Distance ◽  
Protein Tau ◽  
Microtubule Associated Protein Tau ◽  
Behavioral Dynamics ◽  
Cargo Transport ◽  
Cargo Delivery ◽  
Motility Regulation

Many neurodegenerative diseases result from dysfunction of axonal transport, a highly regulated cellular process responsible for site-specific neuronal cargo delivery. The kinesin-3 family member KIF1A is a key mediator of this process by facilitating long-distance cargo delivery in a spatiotemporally regulated manner. While misregulation of KIF1A cargo delivery is observed in many neurodegenerative diseases, the regulatory mechanisms responsible for KIF1A cargo transport are largely unexplored. Our lab has recently characterized a mechanism for a unique pausing behavior of KIF1A in between processive segments on the microtubule. This behavior, mediated through an interaction between the KIF1A K-loop and the polyglutamylated C-terminal tails of tubulin, helps us further understand how KIF1A conducts long-range cargo transport. However, how this pausing behavior is influenced by other regulatory factors on the microtubule is an unexplored concept. The microtubule associated protein Tau is one potential regulator, as altered Tau function is a pathological marker in many neurodegenerative diseases. However, while the effect of Tau on kinesin-1 and -2 has been extensively characterized, its role in regulating KIF1A transport is greatly unexplored at the behavioral level. Using single-molecule imaging, we have identified Tau-mediated regulation of KIF1A pausing behavior and motility. Specifically, our findings imply a competitive interaction between Tau and KIF1A for the C-terminal tails of tubulin. We introduce a new mechanism of Tau-mediated kinesin regulation by inhibiting the ability of KIF1A to use C-terminal tail reliant pauses to connect multiple processive segments into a longer run length. Moreover, we have correlated this regulatory mechanism to the behavioral dynamics of Tau, further elucidating the function of Tau diffusive and static behavioral state on the microtubule surface. In summary, we introduce a new mechanism of Tau-mediated motility regulation, providing insight on how disruptions in axonal transport can lead to disease state pathology.

scholarly journals Stochastic Simulation of Neurofilament Transport in Axons: The “Stop-and-Go” Hypothesis

2005 ◽  
Vol 16 (9) ◽  
pp. 4243-4255 ◽  
Author(s):  
Anthony Brown ◽  
Lei Wang ◽  
Peter Jung
Keyword(s):  
Stochastic Model ◽  
Axonal Transport ◽  
Average Velocity ◽  
Cultured Neurons ◽  
Slow Axonal Transport ◽  
Stop And Go ◽  
Kinetics Of ◽  
Fast Rates ◽  
Neurofilament Transport

According to the “stop-and-go” hypothesis of slow axonal transport, cytoskeletal and cytosolic proteins are transported along axons at fast rates but the average velocity is slow because the movements are infrequent and bidirectional. To test whether this hypothesis can explain the kinetics of slow axonal transport in vivo, we have developed a stochastic model of neurofilament transport in axons. We propose that neurofilaments move in both anterograde and retrograde directions along cytoskeletal tracks, alternating between short bouts of rapid movement and short “on-track” pauses, and that they can also temporarily disengage from these tracks, resulting in more prolonged “off-track” pauses. We derive the kinetic parameters of the model from a detailed analysis of the moving and pausing behavior of single neurofilaments in axons of cultured neurons. We show that the model can match the shape, velocity, and spreading of the neurofilament transport waves obtained by radioisotopic pulse labeling in vivo. The model predicts that axonal neurofilaments spend ∼8% of their time on track and ∼97% of their time pausing during their journey along the axon.

scholarly journals Slow Axonal Transport of Neurofilament Protein in Cultured Neurons

1999 ◽  
Vol 144 (3) ◽  
pp. 447-458 ◽  
Author(s):  
Thomas J. Koehnle ◽  
Anthony Brown
Keyword(s):  
Axonal Transport ◽  
Glass Fibers ◽  
Protein Accumulation ◽  
Cultured Neurons ◽  
Neurofilament Protein ◽  
Slow Axonal Transport ◽  
Metabolic Substrates ◽  
Detergent Extraction ◽  
Fine Glass ◽  
Gradual Accumulation

We have investigated the axonal transport of neurofilament protein in cultured neurons by constricting single axons with fine glass fibers. We observed a rapid accumulation of anterogradely and retrogradely transported membranous organelles on both sides of the constrictions and a more gradual accumulation of neurofilament protein proximal to the constrictions. Neurofilament protein accumulation was dependent on the presence of metabolic substrates and was blocked by iodoacetate, which is an inhibitor of glycolysis. These data indicate that neurofilament protein moves anterogradely in these axons by a mechanism that is directly or indirectly dependent on nucleoside triphosphates. The average transport rate was estimated to be at least 130 μm/h (3.1 mm/d), and ∼90% of the accumulated neurofilament protein remained in the axon after detergent extraction, suggesting that it was present in a polymerized form. Electron microscopy demonstrated that there were an abnormally large number of neurofilament polymers proximal to the constrictions. These data suggest that the neurofilament proteins were transported either as assembled polymers or in a nonpolymeric form that assembled locally at the site of accumulation. This study represents the first demonstration of the axonal transport of neurofilament protein in cultured neurons.

scholarly journals Kinesin Mutations Cause Motor Neuron Disease Phenotypes by Disrupting Fast Axonal Transport in Drosophila

Genetics ◽  
1996 ◽  
Vol 144 (3) ◽  
pp. 1075-1085 ◽  
Author(s):  
Daryl D Hurd ◽  
William M Saxton
Keyword(s):  
Motor Neuron ◽  
Axonal Transport ◽  
Action Potentials ◽  
Light And Electron Microscopy ◽  
Synaptic Membrane ◽  
Slow Axonal Transport ◽  
Fast Axonal Transport ◽  
Motor Neuron Diseases ◽  
Transmitter Secretion ◽  
Axon Terminals

Abstract Previous work has shown that mutation of the gene that encodes the microtubule motor subunit kinesin heavy chain (Khc) in Drosophila inhibits neuronal sodium channel activity, action potentials and neurotransmitter secretion. These physiological defects cause progressive distal paralysis in larvae. To identify the cellular defects that cause these phenotypes, larval nerves were studied by light and electron microscopy. The axons of Khc mutants develop dramatic focal swellings along their lengths. The swellings are packed with fast axonal transport cargoes including vesicles, synaptic membrane proteins, mitochondria and prelysosomal organelles, but not with slow axonal transport cargoes such as cytoskeletal elements. Khc mutations also impair the development of larval motor axon terminals, causing dystrophic morphology and marked reductions in synaptic bouton numbers. These observations suggest that as the concentration of maternally provided wild-type KHC decreases, axonal organelles transported by kinesin periodically stall. This causes organelle jams that disrupt retrograde as well as anterograde fast axonal transport, leading to defective action potentials, dystrophic terminals, reduced transmitter secretion and progressive distal paralysis. These phenotypes parallel the pathologies of some vertebrate motor neuron diseases, including some forms of amyotrophic lateral sclerosis (ALS), and suggest that impaired fast axonal transport is a key element in those diseases.

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