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J Biol Chem. 2018 Nov 9;293(45):17336-17348. doi: 10.1074/jbc.RA118.005316. Epub 2018 Sep 21.

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

Author information

1
From the Department of Chemistry and Biochemistry, University of Denver, Denver, Colorado 80208.
2
the Department of Physics, State Key Laboratory of Surface Physics, Key Laboratory for Computational Physical Science, Ministry of Education, Collaborative Innovation Center of Advanced Microstructures (Nanjing), Fudan University, Shanghai 200433, China.
3
the Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, NCI, National Institutes of Health, Frederick, Maryland 21702, and.
4
the Sackler Institute of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
5
From the Department of Chemistry and Biochemistry, University of Denver, Denver, Colorado 80208, martin.margittai@du.edu.

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 plays a synergistic role. Two disease-associated Tau variants, P301S and P301L, also established strong cross-seeding barriers. EPR analysis indicated that fibrils seeded with truncated and mutated Tau, but not htau40, are structurally disordered in the second half of repeat four and onward. These findings suggest that the disorder in this region diminishes the ability of 4R Tau fibrils to recruit 3R Tau monomers, revealing a new mechanism for Tau cross-seeding barriers.

KEYWORDS:

Alzheimer disease; Tau protein (Tau); amyloid; conformational change; electron paramagnetic resonance (EPR); fibril; prion; protein aggregation; protein structure; seeding barrier; tauopathy

PMID:
30242125
PMCID:
PMC6231118
[Available on 2019-11-09]
DOI:
10.1074/jbc.RA118.005316
[Indexed for MEDLINE]

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