| Title: |
Alzheimer proteopathic tau seeds are biochemically a forme fruste of mature paired helical filaments |
| Authors: |
Kumar, Mukesh; Quittot, Noe; Dujardin, Simon; Schlaffner, Christoph N.; Viode, Arthur; Wiedmer, Anne; Beerepoot, Pieter; Chun, Joshua E.; Glynn, Calina; Fernandes, Analiese R.; Donahue, Cameron; Steen, Judith A.; Hyman, Bradley T. |
| Source: |
ISSN:0006-8950 ; ISSN:1460-2156 ; Brain, vol. 147 (2), (637-648. |
| Publisher Information: |
Oxford University Press (OUP) |
| Publication Year: |
2024 |
| Subject Terms: |
AGGREGATION; CHIP; Clinical Neurology; human Alzheimer disease; Life Sciences & Biomedicine; mass spectrometry; neurodegeneration; Neurosciences; Neurosciences & Neurology; OLIGOMERS; PROPAGATION; proteomics; PTM; Science & Technology; Tau protein; Humans; Neurofibrillary Tangles; Alzheimer Disease; tau Proteins; Protein Processing; Post-Translational; Phosphorylation; 11 Medical and Health Sciences; 17 Psychology and Cognitive Sciences; Neurology & Neurosurgery; 32 Biomedical and clinical sciences; 42 Health sciences; 52 Psychology |
| Description: |
Aggregation prone molecules, such as tau, form both historically well characterized fibrillar deposits (neurofibrillary tangles) and recently identified phosphate-buffered saline (PBS) extract species called proteopathic seeds. Both can cause normal endogenous tau to undergo templated misfolding. The relationship of these seeds to the fibrils that define tau-related diseases is unknown. We characterized the aqueous extractable and sarkosyl insoluble fibrillar tau species derived from human Alzheimer brain using mass spectrometry and in vitro bioassays. Post-translational modifications (PTMs) including phosphorylation, acetylation and ubiquitination are identified in both preparations. PBS extract seed competent tau can be distinguished from sarkosyl insoluble tau by the presence of overlapping, but less abundant, PTMs and an absence of some PTMs unique to the latter. The presence of ubiquitin and other PTMs on the PBS-extracted tau species correlates with the amount of tau in the seed competent size exclusion fractions, with the bioactivity and with the aggressiveness of clinical disease. These results demonstrate that the PTMs present on bioactive, seed competent PBS extract tau species are closely related to, but distinct from, the PTMs of mature paired helical filaments, consistent with the idea that they are a forme fruste of tau species that ultimately form fibrils. ; sponsorship: The work was supported by grants from the Tau Consortium of Rainwater Charitable Foundation (B.T.H. and J.S.), National Institute of Health R56AG061196, RF1AG059789, RF1AG058674 and P30AG062421 (B.T.H.), the Alzheimer's Association [2018-AARF-591935 (S.D.)], the Martin L. and Sylvia Seevak Hoffman Fellowship for Alzheimer's Research (S.D.) and National Institute of Health/National Institute of Neurological Disorders and Stroke U01 5U01NS110438-02 (J.S) (Tau Consortium of Rainwater Charitable Foundation, National Institute of Health|R56AG061196, National Institute of Health|RF1AG059789, National Institute of Health|RF1AG058674, ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
https://lirias.kuleuven.be/handle/20.500.12942/739128; https://doi.org/10.1093/brain/awad378; https://pubmed.ncbi.nlm.nih.gov/38236720 |
| DOI: |
10.1093/brain/awad378 |
| Availability: |
https://lirias.kuleuven.be/handle/20.500.12942/739128; https://hdl.handle.net/20.500.12942/739128; https://doi.org/10.1093/brain/awad378; https://pubmed.ncbi.nlm.nih.gov/38236720 |
| Rights: |
info:eu-repo/semantics/restrictedAccess ; intranet |
| Accession Number: |
edsbas.18E65FF9 |
| Database: |
BASE |