Dataset Information

Molecular features of human pathological Tau distinguish tauopathy-associated dementias (primary cohort FLEXITau)

ABSTRACT: In Alzheimer’s disease (AD), pathological Tau protein shows a progressive accumulation of post-translational modifications (PTMs), reflecting disease severity, progression, and prion-like activity. While many neurodegenerative diseases with dementia display Tau aggregates, the pathological proteoforms of Tau protein from each disease type remain unknown. Here, using quantitative mass spectrometry-based proteomics methods, deep characterization of pathological Tau protein isolated from the brains of 203 human subjects with AD, familial AD (fAD), chronic traumatic encephalopathy (CTE), corticobasal degeneration (CBD), Pick’s disease (PiD), progressive supranuclear palsy (PSP), dementia with Lewy bodies - symptomatic control (DLB), and healthy controls (CTRL) is performed. Unsupervised data analyses and supervised machine learning identify distinct molecular features of pathological Tau for each disease, enabling molecular disease stratification. This study identifies potential disease-specific biomarkers and therapeutic targets for tauopathies and provides critical pharmacokinetics data for therapeutic and disease mechanism studies.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Lewy Body Dementia,Chronic Traumatic Encephalopathy,Progressive Supranuclear Palsy,Alzheimer's Disease,Corticobasal Degeneration Syndrome,Pick's Disease

SUBMITTER: Christoph Schlaffner

LAB HEAD: Judith A. Steen

PROVIDER: PXD069437 | Pride | 2026-02-19

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20210712_MK_MGH_Insol.wiff	Wiff
	20210712_MK_MGH_Insol.wiff.scan	Wiff
	20210713_Insoluble-TauComparision.sky	Other
	20210726_Insoluble-TauComparision-2.sky	Other
	20210726_MK_Insol_Reinject.wiff	Wiff

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Project description:In human neurodegenerative diseases associated with the intracellular aggregation of Tau protein, the ordered cores of Tau filaments adopt distinct folds. Here, we analyze Tau filaments isolated from the brain of individuals affected by Prion-Protein cerebral amyloid angiopathy (PrP-CAA) and Gerstmann-Sträussler-Scheinker (GSS) disease, two genetically determined Prion protein (PrP) amyloidoses characterized by the deposition of PrP amyloid (APrP) in the vessel walls and in the cerebral parenchyma, respectively. A nonsense and a missense mutation in the PRNP gene lead to a premature termination of translation at codon position 160 (Q160Ter) of PrP in PrP-CAA, or to the substitution of an amino acid at residue 198 (F198S) of PrP in GSS. These two diseases have different clinical and pathologic phenotypes; however, in both diseases, neuropathologic analyses have consistently shown the presence of numerous neurofibrillary tangles (NFTs) made of filamentous Tau aggregates in neurons. We report that Tau filaments in PrP-CAA and GSS are composed of 3-repeat and 4-repeat Tau isoforms, having a striking similarity to NFTs in Alzheimer disease (AD). In PrP-CAA, Tau filaments are made of both paired helical filaments (PHFs) and straight filaments (SFs), while in GSS only PHFs were found. Mass spectrometry analyses of Tau filaments extracted from PrP-CAA and GSS brains show the presence of post-translational modifications that are comparable to those seen in Tau aggregates from AD. Cryo-EM analysis reveals that the atomic models of the Tau filaments obtained from PrP-CAA and GSS are identical to those of the Tau filaments from AD, and are therefore distinct from those of Pick disease, chronic traumatic encephalopathy, and corticobasal degeneration. Our data support the hypothesis that in the presence of amyloid deposits and regardless of the primary amino acid sequence of the amyloid protein, similar molecular mechanisms are at play in the formation of identical Tau filaments.

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Molecular features of human pathological Tau distinguish tauopathy-associated dementias (primary cohort FLEXITau)

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