Reducing the RNA binding protein TIA1 protects against tau-mediated neurodegeneration in vivo

Apicco, Daniel J.; Ash, Peter E.A.; Maziuk, Brandon F.; LeBlang, Chelsey Jenna; Medalla, Maria; Abdullatif, Ali Al; Ferragud, Antonio; Botelho, Emily; Ballance, Heather; Dhawan, Uma; Boudeau, Samantha; Cruz, Anna Lourdes; Kashy, Daniel; Wong, Aria; Goldberg, Lisa R.; Yazdani, Neema; Zhang, Cheng; Ung, Choong Yong; Tripodis, Yorghos; Kanaan, Nicholas M.; Ikezu, Tsuneya; Cottone, Pietro; Leszyk, John D.; Li, Hu; Luebke, Jennifer I.; Bryant, Camron D.; Wolozin, Benjamin

doi:10.1038/s41593-017-0022-z

Cited by 207 publications

(272 citation statements)

References 47 publications

Supporting

Mentioning

255

Contrasting

Order By: Relevance

“…The results mirror past studies that found opposing effects on ribosomal gene transcript and protein levels in brain samples from patients with tauopathies [17, 28]. Moreover, these findings are not surprising considering the recruitment of tau–ribosome complexes in stress granules with TIA1 [7, 59] Based on our microarray analysis, we also isolated a pronounced doxycycline effect (Fig. 4f).…”

Section: Discussionsupporting

confidence: 90%

Tau drives translational selectivity by interacting with ribosomal proteins

et al. 2019

View full text Add to dashboard Cite

There is a fundamental gap in understanding the consequences of tau–ribosome interactions. Tau oligomers and filaments hinder protein synthesis in vitro, and they associate strongly with ribosomes in vivo. Here, we investigated the consequences of tau interactions with ribosomes in transgenic mice, in cells, and in human brain tissues to identify tau as a direct modulator of ribosomal selectivity. First, we performed microarrays and nascent proteomics to measure changes in protein synthesis. Using regulatable rTg4510 tau transgenic mice, we determined that tau expression differentially shifts both the transcriptome and the nascent proteome, and that the synthesis of ribosomal proteins is reversibly dependent on tau levels. We further extended these results to human brains and found that tau pathologically interacts with ribosomal protein S6 (rpS6 or S6), a crucial regulator of translation. Consequently, protein synthesis under translational control of rpS6 was reduced under tauopathic conditions in Alzheimer’s disease brains. Our data establish tau as a driver of RNA translation selectivity. Moreover, since regulation of protein synthesis is critical for learning and memory, aberrant tau–ribosome interactions in disease could explain the linkage between tauopathies and cognitive impairment.Electronic supplementary materialThe online version of this article (10.1007/s00401-019-01970-9) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussionsupporting

confidence: 90%

Tau drives translational selectivity by interacting with ribosomal proteins

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Compellingly, KD of Ataxin-2 in an ALS mouse model reduced the number of TDP-43 aggregates in the spinal cord of the affected mice and dramatically extended survival [133]. Similarly, KD of SG protein Tia-1, which is known to interact with Tau, was also shown to prevent Tau pathology and toxicity in neuronal culture and rodent models [134,135]. These observations convincingly demonstrate that targeting phase transitions through ASO technology could be a viable strategy to halt pathological aggregation in TDP-43 and Tau proteinopathies, and possibly in other protein aggregation diseases.…”

Section: Road Toward Novel Therapy?mentioning

confidence: 99%

Protein Phase Separation: A New Phase in Cell Biology

Boeynaems

Alberti

Fawzi

et al. 2018

Trends in Cell Biology

Self Cite

1,629

1,517

View full text Add to dashboard Cite

Cellular compartments and organelles organize biological matter. Most well-known organelles are separated by a membrane boundary from their surrounding milieu. There are also many so-called membraneless organelles and recent studies suggest that these organelles, which are supramolecular assemblies of proteins and RNA molecules, form via protein phase separation. Recent discoveries have shed light on the molecular properties, formation, regulation, and function of membraneless organelles. A combination of techniques from cell biology, biophysics, physical chemistry, structural biology, and bioinformatics are starting to help establish the molecular principles of an emerging field, thus paving the way for exciting discoveries, including novel therapeutic approaches for the treatment of age-related disorders.

show abstract

“…Our data also strongly support a role for mRNA splicing and transport in AD pathogenesis (RNA splicing, FDR = 4.48e-10; RNA transport, FDR = 3.32e-16). RNA binding proteins in these processes have recently emerged as major players in various non-AD neurodegenerative diseases 49 , and recent studies suggested possible involvement in AD (TIA1 protects against tau-mediated degeneration 50 , CELF1 is one of the main GWAS hits 51 , and the activity of ELAVL proteins is altered in AD brains 52 ).…”

Section: Identifying Ad-associated Genes Through Integration Of Ad Gwmentioning

confidence: 99%

Selective neuronal vulnerability in Alzheimer’s disease: a network-based analysis

Roussarie

Yao

Plautz

et al. 2018

Preprint

View full text Add to dashboard Cite

A major obstacle to treating Alzheimer's disease (AD) is our lack of understanding of the molecular mechanisms underlying selective neuronal vulnerability, which is a key characteristic of the disease. Here we present a framework to integrate highquality neuron-type specific molecular profiles across the lifetime of the healthy mouse, which we generated using bacTRAP, with postmortem human functional genomics and quantitative genetics data. We demonstrate human-mouse conservation of cellular taxonomy at the molecular level for AD vulnerable and resistant neurons, identify specific genes and pathways associated with AD pathology, and pinpoint a specific functional gene module underlying selective vulnerability, enriched in processes associated with axonal remodeling, and affected by both amyloid accumulation and aging. Overall, our study provides a molecular framework for understanding the complex interplay between Aβ, aging, and neurodegeneration within the most vulnerable neurons in AD.

show abstract

Reducing the RNA binding protein TIA1 protects against tau-mediated neurodegeneration in vivo

Cited by 207 publications

References 47 publications

Tau drives translational selectivity by interacting with ribosomal proteins

Tau drives translational selectivity by interacting with ribosomal proteins

Protein Phase Separation: A New Phase in Cell Biology

Selective neuronal vulnerability in Alzheimer’s disease: a network-based analysis

Contact Info

Product

Resources

About