Current directions in tau research: Highlights from Tau 2020 DOI Creative Commons
Claire E. Sexton, Heather M. Snyder, Dirk Beher

et al.

Alzheimer s & Dementia, Journal Year: 2021, Volume and Issue: 18(5), P. 988 - 1007

Published: Sept. 28, 2021

Abstract Studies supporting a strong association between tau deposition and neuronal loss, neurodegeneration, cognitive decline have heightened the allure of tau‐related mechanisms as therapeutic targets. In February 2020, leading experts from around world convened for first‐ever Tau2020 Global Conference in Washington, DC, co‐organized cosponsored by Rainwater Charitable Foundation, Alzheimer's Association, CurePSP. Representing academia, industry, government, philanthropic sector, presenters attendees discussed recent advances current directions research. The meeting provided unique opportunity to move research forward fostering global partnerships among other stakeholders providing support new drug discovery programs, groundbreaking research, emerging researchers. also an present critical research‐advancing tools insights that are now rapidly accelerating pace

Language: Английский

Biomarkers for neurodegenerative diseases DOI
Oskar Hansson

Nature Medicine, Journal Year: 2021, Volume and Issue: 27(6), P. 954 - 963

Published: June 1, 2021

Language: Английский

Citations

760
The expanding amyloid family: Structure, stability, function, and pathogenesis DOI Creative Commons
M.R. Sawaya, Michael P. Hughes,

José A. Rodríguez

et al.

Cell, Journal Year: 2021, Volume and Issue: 184(19), P. 4857 - 4873

Published: Sept. 1, 2021

Language: Английский

Citations

279
Tau Post-translational Modifications: Dynamic Transformers of Tau Function, Degradation, and Aggregation DOI Creative Commons
Carolina Alquézar, Shruti Arya, Aimee W. Kao

et al.

Frontiers in Neurology, Journal Year: 2021, Volume and Issue: 11

Published: Jan. 7, 2021

Post-translational modifications (PTMs) on tau have long been recognized as affecting protein function and contributing to neurodegeneration. The explosion of information potential observed PTMs provides an opportunity better understand these in the context homeostasis, which becomes perturbed with aging disease. Prevailing views regard a that undergoes abnormal phosphorylation prior its accumulation into toxic aggregates implicated Alzheimer's disease (AD) other tauopathies. However, may, fact, represent part normal but interrupted catabolism protein. In addition phosphorylation, another forms post-translational modification including (but not limited to), acetylation, ubiquitination, glycation, glycosylation, SUMOylation, methylation, oxidation, nitration. A holistic appreciation how regulate during health are potentially hijacked remains elusive. Recent studies reinforced idea play critical role localization, protein-protein interactions, maintenance levels, modifying aggregate structure. These also provide tantalizing clues possibility neurons actively choose is post-translationally modified, competitive combinatorial ways, achieve broad, cellular programs commensurate distinctive environmental conditions found development, aging, stress, Here, we review describe what currently known about their functional impacts. addition, classify from perspectives electrostatics, stability, all contribute homeostasis. Finally, assess impact solubility aggregation. Tau occupies undoubtedly important position biology neurodegenerative diseases. This aims integrated perspective actively, purposefully, dynamically remodel function, clearance, doing so, hope enable more comprehensive understanding will positively future studies.

Language: Английский

Citations

252
Neuropathology and molecular diagnosis of Synucleinopathies DOI Creative Commons
Shunsuke Koga, Hiroaki Sekiya, Naveen Kondru

et al.

Molecular Neurodegeneration, Journal Year: 2021, Volume and Issue: 16(1)

Published: Dec. 18, 2021

Synucleinopathies are clinically and pathologically heterogeneous disorders characterized by pathologic aggregates of α-synuclein in neurons glia, the form Lewy bodies, neurites, neuronal cytoplasmic inclusions, glial inclusions. can be divided into two major disease entities: body multiple system atrophy (MSA). Common clinical presentations Parkinson's (PD), PD with dementia, dementia bodies (DLB), while MSA has subtypes, predominant cerebellar ataxia parkinsonism. There currently no disease-modifying therapies for synucleinopathies, but information obtained from molecular genetics models that explore mechanisms conversion to oligomers insoluble fibrils offer hope eventual therapies. It remains unclear how associated distinct cellular pathologies (e.g., inclusions) what factors determine neuroanatomical cell type vulnerability. Accumulating evidence vitro vivo experiments suggests species derived "strains" having different seeding properties. Recent advancements assays, such as real-time quaking-induced (RT-QuIC) protein misfolding cyclic amplification (PMCA), not only demonstrate activity also exciting opportunities diagnosis using readily accessible peripheral tissue samples. Cryogenic electron microscopy (cryo-EM) structural studies recombinant or brain-derived filaments provide new insight synucleinopathies. In this review, we describe clinical, genetic neuropathologic features including a discussion evolution classification staging disease. We brief on proposed formation, well supporting existence strains MSA.

Language: Английский

Citations

211
Tau: Enabler of diverse brain disorders and target of rapidly evolving therapeutic strategies DOI
Che-Wei Chang, Qiang Shao, Lennart Mucke

et al.

Science, Journal Year: 2021, Volume and Issue: 371(6532)

Published: Feb. 25, 2021

The many faces of tau protein is implicated in several brain disorders, including Alzheimer's disease, suggesting that it could be a target therapeutics. However, because unclear how the pleiotropic roles lead to neural pathology different diseases, drug development remains challenging. Chang et al. review possible mechanisms diseases and paths forward improving research development. Science , this issue p. eabb8255

Language: Английский

Citations

194
Amyloid-beta peptide and tau protein crosstalk in Alzheimer’s disease DOI Creative Commons
Sandra Villegas,

AlejandroR Roda,

Gabriel Serra-Mir

et al.

Neural Regeneration Research, Journal Year: 2021, Volume and Issue: 17(8), P. 1666 - 1666

Published: Dec. 10, 2021

Alzheimer's disease is a neurodegenerative that accounts for most of the 50-million dementia cases worldwide in 2018. A large amount evidence supports amyloid cascade hypothesis, which states amyloid-beta accumulation triggers tau hyperphosphorylation and aggregation form neurofibrillary tangles, these aggregates lead to inflammation, synaptic impairment, neuronal loss, thus cognitive decline behavioral abnormalities. The poor correlation found between plaques, have led scientific community question whether actually triggering neurodegeneration disease. occurrence tangles better correlates loss clinical symptoms and, although may initiate events, impairment likely effector molecule neurodegeneration. Recently, it has been shown cooperatively work impair transcription genes involved function more importantly, downregulation partially reverses transcriptional perturbations. Despite mounting points an interplay tau, some factors could independently affect both pathologies. Thus, dual pathway there are common upstream causing abnormalities proposed. Among others, immune system seems be strongly Other factors, as apolipoprotein E ε4 isoform suggested act link hyperphosphorylation. Interestingly, amyloid-beta-immunotherapy reduces not only but also levels animal models trials. Likewise, tau-immunotherapy levels. even though immunotherapy advanced than tau-immunotherapy, combined tau-directed therapies at early stages recently proposed strategy stop progression

Language: Английский

Citations

187
Seeded assembly in vitro does not replicate the structures of α‐synuclein filaments from multiple system atrophy DOI Creative Commons
Sofia Lövestam, Manuel Schweighauser, Tomoyasu Matsubara

et al.

FEBS Open Bio, Journal Year: 2021, Volume and Issue: 11(4), P. 999 - 1013

Published: Feb. 6, 2021

The propagation of conformational strains by templated seeding is central to the prion concept. Seeded assembly α-synuclein into filaments believed underlie prion-like spreading protein inclusions in a number human neurodegenerative diseases, including Parkinson's disease, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). We previously determined atomic structures from putamen five individuals MSA. Here, we used filament preparations three these brains for vitro seeded recombinant α-synuclein. find that assemblies differ those seeds, suggesting additional, as yet unknown, factors play role seeds. Identification will be essential understanding proteinopathies.

Language: Английский

Citations

131
Tau-targeting therapies for Alzheimer disease: current status and future directions DOI
Erin E. Congdon, Changyi Ji,

Amber M. Tetlow

et al.

Nature Reviews Neurology, Journal Year: 2023, Volume and Issue: 19(12), P. 715 - 736

Published: Oct. 24, 2023

Language: Английский

Citations

130
Mechanisms and pathology of protein misfolding and aggregation DOI
Nikolaos Louros, Joost Schymkowitz, Frédéric Rousseau

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 24(12), P. 912 - 933

Published: Sept. 8, 2023

Language: Английский

Citations

122
Revisiting the grammar of Tau aggregation and pathology formation: how new insights from brain pathology are shaping how we study and target Tauopathies DOI Creative Commons
Galina Limorenko, Hilal A. Lashuel

Chemical Society Reviews, Journal Year: 2021, Volume and Issue: 51(2), P. 513 - 565

Published: Dec. 10, 2021

We discuss novel approaches for embracing and reproducing complexity of Tau pathology required developing disease-relevant diagnostics effective therapies.

Language: Английский

Citations

117