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Translated retained intron 11 sequence confers pathological properties to Tau in Alzheimer’s disease

ABSTRACT: The pathological aggregation of Tau protein into oligomers and fibrils plays a central role in Alzheimer's disease (AD). Here, we explore the biochemical and cellular properties conferred by a unique 19-amino acid intronic peptide found exclusively in the Tau11i isoform. We demonstrate that this intronic peptide mediates robust formation of high molecular weight (HMW) oligomers that resist denaturing and reducing conditions, distinguishing Tau11i from other Tau isoforms lacking this sequence. Tau11i also uniquely forms stable heterodimers with Tau441, suggesting a role in the propagation of Tau pathology. Additionally, the intronic peptide enhances Tau11i’s liquid-liquid phase separation (LLPS), a critical early event associated with pathological aggregation. In vitro assays showed that Tau11i aggregates into β-sheet-rich fibrils more efficiently than other Tau isoforms, significantly facilitating fibril formation and cellular seeding in Tau biosensor cells. Transcriptomic profiling indicated substantial dysregulation in neuronal pathways involving immune response, synaptic function, and metabolism, with Tau11i-expressing neurons closely mirroring the gene expression patterns of AD neurons, particularly the AT8-negative subtype. Furthermore, Tau11i specifically interacts with stress granule-associated RNA-binding proteins, notably PABPC1, implicating it in stress granule dynamics and RNA homeostasis. Collectively, these findings identify the intronic peptide as a critical factor driving Tau11i-specific oligomerization and early-stage molecular alterations associated with Alzheimer's disease, highlighting its potential as a novel therapeutic target distinct from classic Tau pathology.

ORGANISM(S): Homo sapiens

PROVIDER: GSE294848 | GEO | 2025/12/26

REPOSITORIES: GEO

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Project description:Purpose: Overexpression of tau isoforms has been linked to neurodegenerative diseases, and abnormal tau expression is correlated with genomic instability. The purpose of this study is to use RNA-sequencing and molecular biological techniques to determine if there are any unique genomic consequences associated with overexpression of one or more tau isoforms. Methods: SHSY-5Y cells were infected in triplicate with lentiviruses to induce overexpression of 3R and 4R tau isoforms, were treated with amyloid-beta oligomers or DMSO, and were differentiated into neurons using retinoic acid. After RNA collection via TRIzol, poly(A)-selected, 100 bp, paired-end library preparation and sequencing were completed by the IGM Genomics Center, University of California, San Diego, La Jolla, CA, using an Illumina NovaSeq 6000 that was purchased with funding from a National Institutes of Health SIG grant (#S10 OD026929). Trimmed FASTQ files were aligned to GRCH38 using STAR and differential expression of genes and transposable elements was determined using DESeq2 and software from TEToolkit (available from the Hammell Lab at Cold Spring Harbor Laboratory). Results: Our RNA-seq analysis revealed similar gene and transposable element expression patterns between cells overexpressing tau isoforms and patients with Alzheimer's disease or progressive supranuclear palsy. We found widespread differential expression particularly in L1 and Alu transposable elements and upregulation of genes related to extracellular matrix organization, focal adhesions, and cell junctions, among other biological processes. Conclusions: Our study is the first to our knowledge to examine locus-specific transposable element expression in the context of tauopathies, and to our knowledge is the first to specifically examine transposable element expression stemming from overexpression of tau isoforms. Our study provides additional evidence that transposable elements may play a role in tauopathies and provides further insight into the locations of transposable element expression in the genome in the context of neurodegenerative diseases.

Project description:Yuraszeck2010 - Vulnerabilities in the Tau Network in Tau Pathophysiology This model is described in the article: Vulnerabilities in the tau network and the role of ultrasensitive points in tau pathophysiology. Yuraszeck TM, Neveu P, Rodriguez-Fernandez M, Robinson A, Kosik KS, Doyle FJ 3rd. PLoS Comput. Biol. 2010; 6(11): e1000997 Abstract: The multifactorial nature of disease motivates the use of systems-level analyses to understand their pathology. We used a systems biology approach to study tau aggregation, one of the hallmark features of Alzheimer's disease. A mathematical model was constructed to capture the current state of knowledge concerning tau's behavior and interactions in cells. The model was implemented in silico in the form of ordinary differential equations. The identifiability of the model was assessed and parameters were estimated to generate two cellular states: a population of solutions that corresponds to normal tau homeostasis and a population of solutions that displays aggregation-prone behavior. The model of normal tau homeostasis was robust to perturbations, and disturbances in multiple processes were required to achieve an aggregation-prone state. The aggregation-prone state was ultrasensitive to perturbations in diverse subsets of networks. Tau aggregation requires that multiple cellular parameters are set coordinately to a set of values that drive pathological assembly of tau. This model provides a foundation on which to build and increase our understanding of the series of events that lead to tau aggregation and may ultimately be used to identify critical intervention points that can direct the cell away from tau aggregation to aid in the treatment of tau-mediated (or related) aggregation diseases including Alzheimer's. This model is hosted on BioModels Database and identified by: BIOMD0000000542. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Translated retained intron 11 sequence confers pathological properties to Tau in Alzheimer’s disease

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