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      Tau protein liquid–liquid phase separation can initiate tau aggregation


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          The transition between soluble intrinsically disordered tau protein and aggregated tau in neurofibrillary tangles in Alzheimer's disease is unknown. Here, we propose that soluble tau species can undergo liquid–liquid phase separation ( LLPS) under cellular conditions and that phase‐separated tau droplets can serve as an intermediate toward tau aggregate formation. We demonstrate that phosphorylated or mutant aggregation prone recombinant tau undergoes LLPS, as does high molecular weight soluble phospho‐tau isolated from human Alzheimer brain. Droplet‐like tau can also be observed in neurons and other cells. We found that tau droplets become gel‐like in minutes, and over days start to spontaneously form thioflavin‐S‐positive tau aggregates that are competent of seeding cellular tau aggregation. Since analogous LLPS observations have been made for FUS, hn RNPA1, and TDP43, which aggregate in the context of amyotrophic lateral sclerosis, we suggest that LLPS represents a biophysical process with a role in multiple different neurodegenerative diseases.

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            The neuropathology and neurobiology of traumatic brain injury.

            The acute and long-term consequences of traumatic brain injury (TBI) have received increased attention in recent years. In this Review, we discuss the neuropathology and neural mechanisms associated with TBI, drawing on findings from sports-induced TBI in athletes, in whom acute TBI damages axons and elicits both regenerative and degenerative tissue responses in the brain and in whom repeated concussions may initiate a long-term neurodegenerative process called dementia pugilistica or chronic traumatic encephalopathy (CTE). We also consider how the neuropathology and neurobiology of CTE in many ways resembles other neurodegenerative illnesses such as Alzheimer's disease, particularly with respect to mismetabolism and aggregation of tau, β-amyloid, and TDP-43. Finally, we explore how translational research in animal models of acceleration/deceleration types of injury relevant for concussion together with clinical studies employing imaging and biochemical markers may further elucidate the neurobiology of TBI and CTE. Copyright © 2012 Elsevier Inc. All rights reserved.
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              Proteopathic tau seeding predicts tauopathy in vivo.

              Transcellular propagation of protein aggregates, or proteopathic seeds, may drive the progression of neurodegenerative diseases in a prion-like manner. In tauopathies such as Alzheimer's disease, this model predicts that tau seeds propagate pathology through the brain via cell-cell transfer in neural networks. The critical role of tau seeding activity is untested, however. It is unknown whether seeding anticipates and correlates with subsequent development of pathology as predicted for a causal agent. One major limitation has been the lack of a robust assay to measure proteopathic seeding activity in biological specimens. We engineered an ultrasensitive, specific, and facile FRET-based flow cytometry biosensor assay based on expression of tau or synuclein fusions to CFP and YFP, and confirmed its sensitivity and specificity to tau (∼ 300 fM) and synuclein (∼ 300 pM) fibrils. This assay readily discriminates Alzheimer's disease vs. Huntington's disease and aged control brains. We then carried out a detailed time-course study in P301S tauopathy mice, comparing seeding activity versus histological markers of tau pathology, including MC1, AT8, PG5, and Thioflavin S. We detected robust seeding activity at 1.5 mo, >1 mo before the earliest histopathological stain. Proteopathic tau seeding is thus an early and robust marker of tauopathy, suggesting a proximal role for tau seeds in neurodegeneration.

                Author and article information

                EMBO J
                EMBO J
                The EMBO Journal
                John Wiley and Sons Inc. (Hoboken )
                22 February 2018
                03 April 2018
                22 February 2018
                : 37
                : 7 ( doiID: 10.1002/embj.v37.7 )
                [ 1 ] Department of Neurology Massachusetts General Hospital Harvard Medical School Charlestown MA USA
                [ 2 ] German Center for Neurodegenerative Diseases (DZNE) Bonn Germany
                [ 3 ] Department for Biosystems Science and Engineering ETH Zurich Basel Switzerland
                [ 4 ] Department of Cell & Molecular Biology St. Jude Children's Research Hospital Memphis TN USA
                [ 5 ] Max‐Planck Institute for Molecular Cell Biology & Genetics Dresden Germany
                [ 6 ] Max‐Planck Institute for Metabolism Research Hamburg Outstation c/o DESY Hamburg Germany
                [ 7 ] CAESAR Research Center Bonn Germany
                [ 8 ] Howard Hughes Medical Institute Chevy Chase MD USA
                Author notes
                [*] [* ] Corresponding author. Tel: +1 617 230 7184; E‐mail: swegmann@ 123456mgh.harvard.edu

                Corresponding author. Tel: +1 617 726 3987; E‐mail: bhyman@ 123456mgh.harvard.edu


                These authors contributed equally to this work

                © 2018 The Authors. Published under the terms of the CC BY NC ND 4.0 license

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                Page count
                Figures: 12, Tables: 0, Pages: 21, Words: 18820
                Funded by: Massachusetts Alzheimer Disease Research Center
                Award ID: P50AG005134
                Funded by: Howard Hughes Medical Institute (HHMI)
                Award ID: R35NS097974
                Funded by: Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE)
                Funded by: Max‐Planck‐Gesellschaft (MPG)
                Custom metadata
                03 April 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.3.4 mode:remove_FC converted:03.04.2018

                Molecular biology
                aggregation,alzheimer's disease,liquid–liquid phase separation,phosphorylation,tau,physiology,protein biosynthesis & quality control


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