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 Regulation of KIF1A motility via polyglutamylation of tubulin C-terminal tails

2018 ◽  
Author(s):  
Dominique V. Lessard ◽  
Oraya J. Zinder ◽  
Takashi Hotta ◽  
Kristen J. Verhey ◽  
Ryoma Ohi ◽  
...  
Keyword(s):  
Axonal Transport ◽  
Single Molecule ◽  
Posttranslational Modifications ◽  
Molecular Motors ◽  
Regulatory Mechanism ◽  
Traffic Signals ◽  
Cargo Delivery ◽  
Motility Regulation ◽  
Initial Interaction ◽  
Positively Charged

ABSTRACTAxonal transport is a highly regulated cellular process responsible for site-specific neuronal cargo delivery. This process is mediated in part by KIF1A, a member of the kinesin-3 family of molecular motors. It is imperative that KIF1A’s highly efficient, superprocessive motility along microtubules is tightly regulated as misregulation of KIF1A cargo delivery is observed in many neurodegenerative diseases. However, the regulatory mechanisms responsible for KIF1A’s motility, and subsequent proper spatiotemporal cargo delivery, are largely unknown. One potential regulatory mechanism of KIF1A motility is through the posttranslational modifications (PTMs) of axonal microtubules. These PTMs, often occurring on the C-terminal tails of the microtubule tracks, act as molecular “traffic signals” helping to direct kinesin motor cargo delivery. Occurring on neuronal microtubules, C-terminal tail polygutamylation is known to be important for KIF1A cargo transport. KIF1A’s initial interaction with microtubule C-terminal tails is facilitated by the K-loop, a positively charged surface loop of the KIF1A motor domain. However, the K-loop’s role in KIF1A motility and response to perturbations in C-terminal tail polyglutamylation is underexplored. Using single-molecule imaging, we present evidence of KIF1A’s previously unreported pausing behavior on multiple microtubule structures. Further analysis revealed that these pauses link multiple processive segments together, contributing to KIF1A’s characteristic superprocessive run length. We further demonstrate that KIF1A pausing is mediated by a K-loop/polyglutamylated C-terminal tail interaction and is a regulatory mechanism of KIF1A motility. In summary, we introduce a new mechanism of KIF1A motility regulation, providing further insight into KIF1A’s role in axonal transport.

scholarly journals Heparin-induced tau filaments are polymorphic and differ from those in Alzheimer’s and Pick’s diseases

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Wenjuan Zhang ◽  
Benjamin Falcon ◽  
Alexey G Murzin ◽  
Juan Fan ◽  
R Anthony Crowther ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Neurodegenerative Diseases ◽  
Protein Tau ◽  
Microtubule Associated Protein Tau ◽  
The Third ◽  
In Vitro Assembly ◽  
Immuno Electron Microscopy ◽  
Structural Versatility ◽  
Filamentous Inclusions

Assembly of microtubule-associated protein tau into filamentous inclusions underlies a range of neurodegenerative diseases. Tau filaments adopt different conformations in Alzheimer’s and Pick’s diseases. Here, we used cryo- and immuno- electron microscopy to characterise filaments that were assembled from recombinant full-length human tau with four (2N4R) or three (2N3R) microtubule-binding repeats in the presence of heparin. 2N4R tau assembles into multiple types of filaments, and the structures of three types reveal similar ‘kinked hairpin’ folds, in which the second and third repeats pack against each other. 2N3R tau filaments are structurally homogeneous, and adopt a dimeric core, where the third repeats of two tau molecules pack in a parallel manner. The heparin-induced tau filaments differ from those of Alzheimer’s or Pick’s disease, which have larger cores with different repeat compositions. Our results illustrate the structural versatility of amyloid filaments, and raise questions about the relevance of in vitro assembly.

scholarly journals From genetics to pathology: tau and a–synuclein assemblies in neurodegenerative diseases

2001 ◽  
Vol 356 (1406) ◽  
pp. 213-227 ◽  
Author(s):  
Michel Goedert ◽  
Maria Grazia Spillantini ◽  
Louise C. Serpell ◽  
John Berriman ◽  
Michael J. Smith ◽  
...  
Keyword(s):  
Human Brain ◽  
Neurodegenerative Diseases ◽  
Frontotemporal Dementia ◽  
Glial Cells ◽  
Tau Protein ◽  
Nerve Cells ◽  
Degenerative Diseases ◽  
Protein Tau ◽  
Microtubule Associated Protein Tau ◽  
Filamentous Inclusions

The most common degenerative diseases of the human brain are characterized by the presence of abnormal filamentous inclusions in affected nerve cells and glial cells. These diseases can be grouped into two classes, based on the identity of the major proteinaceous components of the filamentous assemblies. The filaments are made of either the microtubule–associated protein tau or the protein α–synuclein. Importantly, the discovery of mutations in the tau gene in familial forms of frontotemporal dementia and of mutations in the α–synuclein gene in familial forms of Parkinson's disease has established that dysfunction of tau protein and α–synuclein can cause neurodegeneration.

scholarly journals Microglia become hypofunctional and release metalloproteases and tau seeds after phagocytosing live neurons with P301S tau aggregates

2021 ◽  
Author(s):  
Maria Grazia Spillantini ◽  
Jack H Brelstaff ◽  
Matthew Mason ◽  
Taxiarchis Katsinelos ◽  
William A McEwan ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Neurodegenerative Diseases ◽  
Matrix Remodeling ◽  
Matrix Metalloprotease ◽  
Protein Tau ◽  
Microtubule Associated Protein Tau ◽  
Senescent Phenotype ◽  
Human Brains ◽  
Tau Aggregate

The microtubule-associated protein tau aggregates in multiple neurodegenerative diseases, causing inflammation and changing the inflammatory signature of microglia by unknown mechanisms. We have shown that microglia phagocytose live neurons containing tau aggregates cultured from P301S tau transgenic mice due to neuronal tau aggregate-induced exposure of the 'eat me' signal phosphatidylserine. Here we show that after phagocytosis, microglia become hypophagocytic while releasing seed-competent insoluble tau aggregates. These microglia activate acidic β-galactosidase, and release senescence-associated cytokines and matrix remodeling enzymes alongside tau, indicating a senescent phenotype. In particular, the marked NFκB-induced activation of matrix metalloprotease 3 (MMP3/stromelysin1) was replicated in the brains of P301S mutant tau transgenic mice, and in human brains from tauopathy patients. These data show that microglia that have been activated to ingest live neurons with tau aggregates behave hormetically, becoming hypofunctional while acting as vectors of tau aggregate spreading.

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 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

scholarly journals Heparin-induced tau filaments are polymorphic and differ from those in Alzheimer’s and Pick’s diseases

2018 ◽  
Author(s):  
Wenjuan Zhang ◽  
Benjamin Falcon ◽  
Alexey G. Murzin ◽  
Juan Fan ◽  
R. Anthony Crowther ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Neurodegenerative Diseases ◽  
Microtubule Binding ◽  
Protein Tau ◽  
Microtubule Associated Protein Tau ◽  
The Third ◽  
Negative Stain ◽  
Different Types ◽  
Filamentous Inclusions

AbstractThe assembly of microtubule-associated protein tau into abundant filamentous inclusions underlies a range of neurodegenerative diseases. The finding that tau filaments adopt different conformations in Alzheimer’s and Pick’s diseases raises the question of what kinds of structures of tau filaments form in vitro. Here, we used electron cryo-microscopy (cryo-EM) and negative-stain immuno-gold electron microscopy (immuno-EM) to characterise filaments that were assembled from recombinant full-length human tau with four (2N4R) or three (2N3R) microtubule-binding repeats in the presence of heparin. 4R tau assembles into at least four different types of filaments. Cryo-EM structures of three types of 4R filaments reveal similar “kinked hairpin” folds, in which the second and third repeats pack against each other. 3R tau filaments are structurally homogeneous, and adopt a dimeric core, where the third repeats of two tau molecules pack against each other in a parallel, yet asymmetric, manner. None of the heparin-induced tau filaments resemble those of Alzheimer’s or Pick’s disease, which have larger cores with different repeat compositions. Our results indicate that tau filaments are structurally versatile, and raise questions about the relevance of in vitro assembled amyloids.

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