Structural disorder in four-repeat Tau fibrils reveals a new mechanism for barriers to cross-seeding of Tau isoforms

The Journal of Biological Chemistry
Hilary A WeismillerMartin Margittai

Abstract

The intracellular deposition of fibrils composed of the microtubule-associated protein Tau is a characteristic feature of Alzheimer's disease (AD) and other fatal neurodegenerative disorders collectively known as tauopathies. Short Tau fibrils spread intracerebrally through transfer between interconnected neurons. Once taken up by a recipient cell, Tau fibrils recruit Tau monomers onto their ends. Based on the number of microtubule-binding repeats, there are two distinct groups of Tau isoforms: three-repeat (3R) Tau and four-repeat (4R) Tau. In AD, all Tau isoforms are deposited, whereas in other tauopathies, only 3R or 4R Tau isoforms are deposited. The molecular basis for these isoform-specific depositions is poorly understood, although conformation-based cross-seeding barriers are key. Here, we used sedimentation assays, EPR spectroscopy, and other structural readouts to better understand the cross-seeding barriers of 4R Tau fibrils. We observed that fibrils formed from truncated Tau (K18), but not full-length Tau (htau40), exhibit a barrier that inhibits 3R Tau recruitment. Investigating an array of differently sized fragments, we found that the Tau C terminus modulates the cross-seeding barrier and that the N terminus play...Continue Reading

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Citations

Mar 25, 2020·Physical Chemistry Chemical Physics : PCCP·Qiong-Qiong YaoSarah Perrett
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Apr 30, 2021·Journal of Neurology·Yun WeiDongxin Wang
May 8, 2021·Royal Society Open Science·Emilie N LiuZhefeng Guo
May 26, 2021·Journal of Chemical Information and Modeling·Huan HeFeng Ding
Aug 3, 2021·The Journal of Biological Chemistry·Hilary A WeismillerMartin Margittai
Nov 5, 2021·ACS Chemical Neuroscience·Hao LiJin Yong Lee

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