Distinct Conformations, Aggregation and Cellular Internalization of Different Tau Strains
(2019) In Frontiers in Cellular Neuroscience 13.- 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... (More)
- 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. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/c2c124d7-f9f0-413e-9a28-ca5741f0eed1
- author
- Karikari, Thomas K.
; Nagel, David
; Grainger, Alastair
; Clarke-Bland, Charlotte
; Crowe, James Aaron
LU
; Hill, Eric J and Moffat, Kevin G
- publishing date
- 2019-07-09
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Tau, Fronto-temporal dementia, iPSC
- in
- Frontiers in Cellular Neuroscience
- volume
- 13
- article number
- 296
- publisher
- Frontiers Media S. A.
- external identifiers
-
- scopus:85069496206
- ISSN
- 1662-5102
- DOI
- 10.3389/fncel.2019.00296
- language
- English
- LU publication?
- no
- id
- c2c124d7-f9f0-413e-9a28-ca5741f0eed1
- date added to LUP
- 2022-01-25 11:04:21
- date last changed
- 2022-04-27 07:17:26
@article{c2c124d7-f9f0-413e-9a28-ca5741f0eed1, 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.}}, author = {{Karikari, Thomas K. and Nagel, David and Grainger, Alastair and Clarke-Bland, Charlotte and Crowe, James Aaron and Hill, Eric J and Moffat, Kevin G}}, issn = {{1662-5102}}, keywords = {{Tau; Fronto-temporal dementia; iPSC}}, language = {{eng}}, month = {{07}}, publisher = {{Frontiers Media S. A.}}, series = {{Frontiers in Cellular Neuroscience}}, title = {{Distinct Conformations, Aggregation and Cellular Internalization of Different Tau Strains}}, url = {{http://dx.doi.org/10.3389/fncel.2019.00296}}, doi = {{10.3389/fncel.2019.00296}}, volume = {{13}}, year = {{2019}}, }