Emergence of directional bias in tau deposition from axonal transport dynamics.

Defects in axonal transport may partly underpin the differences between the observed pathophysiology of Alzheimer's disease (AD) and that of other non-amyloidogenic tauopathies. Particularly, pathological tau variants may have molecular properties that dysregulate motor proteins responsible for...

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Autores principales:	Justin Torok, Pedro D Maia, Parul Verma, Christopher Mezias, Ashish Raj
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/24834eed861e4290ab95264ca3a273d1
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spelling	oai:doaj.org-article:24834eed861e4290ab95264ca3a273d12021-12-02T19:57:22ZEmergence of directional bias in tau deposition from axonal transport dynamics.1553-734X1553-735810.1371/journal.pcbi.1009258https://doaj.org/article/24834eed861e4290ab95264ca3a273d12021-07-01T00:00:00Zhttps://doi.org/10.1371/journal.pcbi.1009258https://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Defects in axonal transport may partly underpin the differences between the observed pathophysiology of Alzheimer's disease (AD) and that of other non-amyloidogenic tauopathies. Particularly, pathological tau variants may have molecular properties that dysregulate motor proteins responsible for the anterograde-directed transport of tau in a disease-specific fashion. Here we develop the first computational model of tau-modified axonal transport that produces directional biases in the spread of tau pathology. We simulated the spatiotemporal profiles of soluble and insoluble tau species in a multicompartment, two-neuron system using biologically plausible parameters and time scales. Changes in the balance of tau transport feedback parameters can elicit anterograde and retrograde biases in the distributions of soluble and insoluble tau between compartments in the system. Aggregation and fragmentation parameters can also perturb this balance, suggesting a complex interplay between these distinct molecular processes. Critically, we show that the model faithfully recreates the characteristic network spread biases in both AD-like and non-AD-like mouse tauopathy models. Tau transport feedback may therefore help link microscopic differences in tau conformational states and the resulting variety in clinical presentations.Justin TorokPedro D MaiaParul VermaChristopher MeziasAshish RajPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 17, Iss 7, p e1009258 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Justin Torok Pedro D Maia Parul Verma Christopher Mezias Ashish Raj Emergence of directional bias in tau deposition from axonal transport dynamics.
description	Defects in axonal transport may partly underpin the differences between the observed pathophysiology of Alzheimer's disease (AD) and that of other non-amyloidogenic tauopathies. Particularly, pathological tau variants may have molecular properties that dysregulate motor proteins responsible for the anterograde-directed transport of tau in a disease-specific fashion. Here we develop the first computational model of tau-modified axonal transport that produces directional biases in the spread of tau pathology. We simulated the spatiotemporal profiles of soluble and insoluble tau species in a multicompartment, two-neuron system using biologically plausible parameters and time scales. Changes in the balance of tau transport feedback parameters can elicit anterograde and retrograde biases in the distributions of soluble and insoluble tau between compartments in the system. Aggregation and fragmentation parameters can also perturb this balance, suggesting a complex interplay between these distinct molecular processes. Critically, we show that the model faithfully recreates the characteristic network spread biases in both AD-like and non-AD-like mouse tauopathy models. Tau transport feedback may therefore help link microscopic differences in tau conformational states and the resulting variety in clinical presentations.
format	article
author	Justin Torok Pedro D Maia Parul Verma Christopher Mezias Ashish Raj
author_facet	Justin Torok Pedro D Maia Parul Verma Christopher Mezias Ashish Raj
author_sort	Justin Torok
title	Emergence of directional bias in tau deposition from axonal transport dynamics.
title_short	Emergence of directional bias in tau deposition from axonal transport dynamics.
title_full	Emergence of directional bias in tau deposition from axonal transport dynamics.
title_fullStr	Emergence of directional bias in tau deposition from axonal transport dynamics.
title_full_unstemmed	Emergence of directional bias in tau deposition from axonal transport dynamics.
title_sort	emergence of directional bias in tau deposition from axonal transport dynamics.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/24834eed861e4290ab95264ca3a273d1
work_keys_str_mv	AT justintorok emergenceofdirectionalbiasintaudepositionfromaxonaltransportdynamics AT pedrodmaia emergenceofdirectionalbiasintaudepositionfromaxonaltransportdynamics AT parulverma emergenceofdirectionalbiasintaudepositionfromaxonaltransportdynamics AT christophermezias emergenceofdirectionalbiasintaudepositionfromaxonaltransportdynamics AT ashishraj emergenceofdirectionalbiasintaudepositionfromaxonaltransportdynamics
_version_	1718375829071724544

Emergence of directional bias in tau deposition from axonal transport dynamics.

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