9BXR

Straight Filaments purified from Down Syndrome individual brain tissue applied to graphene oxide antibody affinity grids

9BXR の概要

• エントリーDOI: 10.2210/pdb9bxr/pdb
• EMDBエントリー: 45009
• 分子名称: Microtubule-associated protein tau (1 entity in total)
• 機能のキーワード: amyloid, filament, neurodegeneration, down syndrome, protein fibril
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 50223.47

構造登録者

Tse, E.,Ghosh, U.,Condello, C.,Southworth, D. (登録日: 2024-05-22, 公開日: 2024-08-14)

主引用文献

Ghosh, U.,Tse, E.,Yang, H.,Shi, M.,Caro, C.D.,Wang, F.,Merz, G.E.,Prusiner, S.B.,Southworth, D.R.,Condello, C.
Cryo-EM structures reveal tau filaments from Down syndrome adopt Alzheimer's disease fold.
Acta Neuropathol Commun, 12:94-94, 2024

PubMed Abstract: Down syndrome (DS) is a common genetic condition caused by trisomy of chromosome 21. Among their complex clinical features, including musculoskeletal, neurological, and cardiovascular disabilities, individuals with DS have an increased risk of developing progressive dementia and early-onset Alzheimer's disease (AD). This dementia is attributed to the increased gene dosage of the amyloid-β (Aβ) precursor protein gene, the formation of self-propagating Aβ and tau prion conformers, and the deposition of neurotoxic Aβ plaques and tau neurofibrillary tangles. Tau amyloid fibrils have previously been established to adopt many distinct conformations across different neurodegenerative conditions. Here, we report the characterization of brain samples from four DS cases spanning 36-63 years of age by spectral confocal imaging with conformation-specific dyes and cryo-electron microscopy (cryo-EM) to determine structures of isolated tau fibrils. High-resolution structures revealed paired helical filament (PHF) and straight filament (SF) conformations of tau that were identical to those determined from AD cases. The PHFs and SFs are made of two C-shaped protofilaments, each containing a cross-β/β-helix motif. Similar to filaments from AD cases, most filaments from the DS cases adopted the PHF form, while a minority (approximately 20%) formed SFs. Samples from the youngest individual with no documented dementia had sparse tau deposits. To isolate tau for cryo-EM from this challenging sample we used a novel affinity-grid method involving a graphene oxide surface derivatized with anti-tau antibodies. This method improved isolation and revealed that primarily tau PHFs and a minor population of chronic traumatic encephalopathy type II-like filaments were present in this youngest case. These findings expand the similarities between AD and DS to the molecular level, providing insight into their related pathologies and the potential for targeting common tau filament folds by small-molecule therapeutics and diagnostics.

PubMed: 38867338
DOI: 10.1186/s40478-024-01806-y

実験手法

ELECTRON MICROSCOPY (3.2 Å)