To elucidate the role of Tau isoforms and post-translational modification (PTM) stoichiometry in Alzheimer's disease (AD), we generated a high-resolution quantitative proteomics map of 95 PTMs on multiple isoforms of Tau isolated from postmortem human tissue from 49 AD and 42 control subjects. Although Tau PTM maps reveal heterogeneity across subjects, a subset of PTMs display high occupancy and frequency for AD, suggesting importance in disease. Unsupervised analyses indicate that PTMs occur in an ordered manner, leading to Tau aggregation. The processive addition and minimal set of PTMs associated with seeding activity was further defined by analysis of size-fractionated Tau. To summarize, features in the Tau protein critical for disease intervention at different stages of disease are identified, including enrichment of 0N and 4R isoforms, underrepresentation of the C terminus, an increase in negative charge in the proline-rich region (PRR), and a decrease in positive charge in the microtubule binding domain (MBD).
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168922 | PMC |
| http://dx.doi.org/10.1016/j.cell.2020.10.029 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Lactylation of tau in human Alzheimer's disease brains.
Alzheimers Dement
December 2024
Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, Kansas, USA.
Introduction: Aggregation of hyperphosphorylated tau (tauopathy) is associated with cognitive impairment in patients with Alzheimer's disease (AD). In AD, a metabolic shift due to the Warburg effect results in increased lactate production. Lactate can induce a post-translational modification (PTM) on proteins that conjugates lactyl groups to lysine (K) residues, which is known as lactylation.
View Article and Find Full Text PDFDementia with lewy bodies patients with high tau levels display unique proteome profiles.
Mol Neurodegener
December 2024
F.M. Kirby Neurobiology Center, Department of Neurobiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Background: Clinical studies have long observed that neurodegenerative disorders display a range of symptoms and pathological features and, in some cases, overlap, suggesting that these diseases exist on a spectrum. Dementia with Lewy Bodies (DLB), a synucleinopathy, is a prominent example, where symptomatic similarities with tauopathy, Alzheimer's disease, are observed. Although tau pathology has been observed in DLB, the interplay between tau and α-synuclein is poorly understood at a molecular level.
View Article and Find Full Text PDFUnveiling Histone Proteoforms using 2D-TAU Gel Electrophoresis.
J Vis Exp
October 2024
Research Center on Advanced Biochemistry and Molecular Biology, Department of Experimental and Clinical Medicine, Magna Græcia University of Catanzaro;
Article Synopsis
- Histones undergo various post-translational modifications (PTMs) that affect nucleosome dynamics and cell fate, with histone PTM regulation being essential for normal cellular function.
- The method described combines two types of gel electrophoresis—TAU-GEL and SDS-PAGE—to effectively isolate and analyze histone isoforms, providing a detailed two-dimensional map.
- This innovative proteomic technique enhances the ability to enrich specific histone isoforms and characterize new PTMs, aiding in the understanding of abnormal cellular behaviors linked to histone deregulation.
Development and characterization of novel anti-acetylated tau monoclonal antibodies to probe pathogenic tau species in Alzheimer's disease.
Acta Neuropathol Commun
October 2024
Department of Neurology, UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
Article Synopsis
- * Recent research highlights tau acetylation as a significant post-translational modification that influences both normal tau activity and its potentially harmful aggregation in tauopathies, particularly in specific brain regions affected by Alzheimer's.
- * The study involved creating precise monoclonal antibodies that target acetylated tau and successfully validating their use in neurons, providing valuable tools for understanding tau behavior and possibly advancing diagnostics or treatments for tau-related diseases.
Pilot Study for Deciphering Post-Translational Modifications and Proteoforms of Tau Protein by Capillary Electrophoresis-Mass Spectrometry.
J Proteome Res
November 2024
Department of Chemistry, Michigan State University, 578 S Shaw Lane, East Lansing, Michigan 48824, United States.
Article Synopsis
- Abnormal tau protein accumulation is a key feature of Alzheimer's disease, with various post-translational modifications (PTMs) such as phosphorylation contributing to the disease's progression.
- A pilot study used complementary techniques, CZE-MS/MS and RPLC-MS/MS, to analyze recombinant human tau-0N3R, resulting in the identification of 50 phosphorylation sites, which is 25% more than RPLC-MS/MS could find alone.
- The study also introduced capillary isoelectric focusing (cIEF)-MS, revealing multiple tau-0N3R proteoforms, some with up to nine phosphorylation sites, highlighting the effectiveness of these techniques for studying tau's complexity and potential dimerization.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!