Karikari, Thomas K., Nagel, David A., Grainger, Alastair, Clarke-Bland, Charlotte, Crowe, James, Hill, Eric J. and Moffat, Kevin G. (2019) Distinct conformations, aggregation and cellular internalization of different tau strains. Frontiers in Cellular Neuroscience, 13 . 296. doi:10.3389/fncel.2019.00296 ISSN 1662-5102.

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Abstract

The inter-cellular propagation of tau aggregates in several neurodegenerative diseases involves, in part, recurring cycles of extracellular tau uptake, initiation of endogenous tau aggregation, and extracellular release of at least part of this protein complex. However, human brain tau extracts from diverse tauopathies exhibit variant or “strain” specificity in inducing inter-cellular propagation in both cell and animal models. It is unclear if these distinctive properties are affected by disease-specific differences in aggregated tau conformation and structure. We have used a combined structural and cell biological approach to study if two frontotemporal dementia (FTD)-associated pathologic mutations, V337M and N279K, affect the aggregation, conformation and cellular internalization of the tau four-repeat domain (K18) fragment. In both heparin-induced and native-state aggregation experiments, each FTD variant formed soluble and fibrillar aggregates with remarkable morphological and immunological distinctions from the wild type (WT) aggregates. Exogenously applied oligomers of the FTD tau-K18 variants (V337M and N279K) were significantly more efficiently taken up by SH-SY5Y neuroblastoma cells than WT tau-K18, suggesting mutation-induced changes in cellular internalization. However, shared internalization mechanisms were observed: endocytosed oligomers were distributed in the cytoplasm and nucleus of SH-SY5Y cells and the neurites and soma of human induced pluripotent stem cell-derived neurons, where they co-localized with endogenous tau and the nuclear protein nucleolin. Altogether, evidence of conformational and aggregation differences between WT and disease-mutated tau K18 is demonstrated, which may explain their distinct cellular internalization potencies. These findings may account for critical aspects of the molecular pathogenesis of tauopathies involving WT and mutated tau.

Item Type:	Journal Article
Subjects:	Q Science > QD Chemistry Q Science > QP Physiology R Medicine > RC Internal medicine
Divisions:	Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- )
Library of Congress Subject Headings (LCSH):	Proteins -- Laboratory manuals, Alzheimer's disease, Frontotemporal dementia, Oligomers
Journal or Publication Title:	Frontiers in Cellular Neuroscience
Publisher:	Frontiers Research Foundation
ISSN:	1662-5102
Official Date:	9 July 2019
Dates:	Date Event 9 July 2019 Published 18 June 2019 Accepted
Volume:	13
Article Number:	296
DOI:	10.3389/fncel.2019.00296
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Date of first compliant deposit:	22 July 2019
Date of first compliant Open Access:	23 July 2019
RIOXX Funder/Project Grant:	Project/Grant ID RIOXX Funder Name Funder ID CRACK IT: Untanglegrant (NC/C013101/1) National Centre for the Replacement Refinement and Reduction of Animals in Research UNSPECIFIED Chancellor’s Scholarship University of Warwick http://dx.doi.org/10.13039/501100000741 BB/J014532/1 [BBSRC] Biotechnology and Biological Sciences Research Council http://dx.doi.org/10.13039/501100000268

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