The sulfation code of tauopathies: heparan sulfate proteoglycans in the prion like spread of tau pathology

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Mah, Dylan
Zhao, Jing
Liu, Xinyue
Zhang, Fuming
Liu, Jian
Wang, Lianchun
Linhardt, Robert J.
Wang, Chunyu
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Biology , Chemistry and chemical biology , Chemical and biological engineering , Biomedical engineering
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Tauopathies are a heterogenous family of progressive neurodegenerative diseases defined by the appearance of proteinaceous lesions within the brain composed of abnormally folded species of Microtubule Associated Protein Tau (tau). Alzheimer's Disease (AD), the most common tauopathy, is the leading cause of cognitive decline among the elderly and is responsible for more than half of all cases of senile dementia worldwide. The characteristic pathology of many tauopathies-AD included-presents as Neurofibrillary Tangles (NFTs), insoluble inclusions found within the neurons of the central nervous system composed primarily of tau protein arranged into Paired Helical Fibrils (PHFs). The spatial extent of this pathology evolves in a remarkably consistent pattern over the course of disease progression. Among the leading hypotheses which seek to explain the stereotypical progression of tauopathies is the prion model, which proposes that the spread of tau pathology is mediated by the transmission of self-propagating tau conformers between cells in a fashion analogous to the mechanism of communicable prion diseases. Protein-glycan interactions between tau and Heparan Sulfate Proteoglycans (HSPGs) have been implicated as a key facilitator in each stage of the prion-like propagation of tau pathology, from the initial secretion of intracellular tau protein into the extracellular matrix, to the uptake of pathogenic tau seeds by cells, and the self-assembly of tau into higher order aggregates. In this review we outline the biochemical basis of the tau-HS interaction and discuss our current understanding of the mechanisms by which these interactions contribute to the propagation of tau pathology in tauopathies, with a particular focus on AD.
Frontiers in Molecular Biosciences, Molecular Recognition, 7, 594497
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The sulfation code of tauopathies: heparan sulfate proteoglycans in the prion like spread of tau pathology, D. J. Mah, J. Zhao, X. Liu, F. Zhang, J. Liu, L. Wang, R. J. Linhardt, C. Wang, Frontiers in Molecular Biosciences, Molecular Recognition, 7, 594497, 2021.
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