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Dysregulated coordination of MAPT exon 2 and exon 10 splicing underlies different tau pathologies in PSP and AD

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Abstract

Understanding regulation of MAPT splicing is important to the etiology of many nerurodegenerative diseases, including Alzheimer disease (AD) and progressive supranuclear palsy (PSP), in which different tau isoforms accumulate in pathologic inclusions. MAPT, the gene encoding the tau protein, undergoes complex alternative pre-mRNA splicing to generate six isoforms. Tauopathies can be categorized by the presence of tau aggregates containing either 3 (3R) or 4 (4R) microtubule-binding domain repeats (determined by inclusion/exclusion of exon 10), but the role of the N-terminal domain of the protein, determined by inclusion/exclusion of exons 2 and 3 has been less well studied. Using a correlational screen in human brain tissue, we observed coordination of MAPT exons 2 and 10 splicing. Expressions of exon 2 splicing regulators and subsequently exon 2 inclusion are differentially disrupted in PSP and AD brain, resulting in the accumulation of 1N4R isoforms in PSP and 0N isoforms in AD temporal cortex. Furthermore, we identified different N-terminal isoforms of tau present in neurofibrillary tangles, dystrophic neurites and tufted astrocytes, indicating a role for differential N-terminal splicing in the development of disparate tau neuropathologies. We conclude that N-terminal splicing and combinatorial regulation with exon 10 inclusion/exclusion is likely to be important to our understanding of tauopathies.

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Acknowledgements

This work was supported by funding from the BrightFocus Foundation (KRB), Association for Frontotemporal Degeneration (KRB), CurePSP (KRB), the Rainwater Charitable Foundation (AMG, KRB), and Alzheimer’s Association AARF-17-529888 (JDC). We thank the NIH Neurobiobanks at the University of Maryland, Harvard and Mount Sinai for supplying tissues for analyses. We also thank the Neuropathology brain bank and research CoRE and the Genetics CoRE at the Icahn School of Medicine at Mt. Sinai for supplying tissues and conducting immunohistochemical staining, and for carrying out targeted iso-seq and data analysis. We are grateful to the study participants and their families for their contributions to research.

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Authors and Affiliations

  1. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Kathryn R. Bowles, Derian A. Pugh, Laura-Maria Oja, Benjamin M. Jadow, Towfique Raj & Alison M. Goate

  2. Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Kathryn R. Bowles, Derian A. Pugh, Laura-Maria Oja, Benjamin M. Jadow, Kurt Farrell, Kristen Whitney, Abhijeet Sharma, Towfique Raj, Ana C. Pereira, John F. Crary & Alison M. Goate

  3. Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Kurt Farrell, Kristen Whitney & John F. Crary

  4. Boston University Alzheimer’s Disease and CTE Center, Boston University School of Medicine, Boston, MA, USA

    Jonathan D. Cherry

  5. Department of Neurology, Boston University School of Medicine, Boston, MA, USA

    Jonathan D. Cherry

  6. VA Boston Healthcare System, 150 S. Huntington Avenue, Boston, MA, USA

    Jonathan D. Cherry

  7. Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA

    Jonathan D. Cherry

  8. Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Abhijeet Sharma, Towfique Raj, Ana C. Pereira & Alison M. Goate

  9. Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Towfique Raj & Ana C. Pereira

  10. Neuropathology Brain Bank and Research Core, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    John F. Crary

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  1. Kathryn R. Bowles
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Contributions

Conceptualization: KRB, AMG. Methodology: KRB, DAP, LMO, BMJ, KF, KW, AS, JDC. Validation: KRB, DAP, LMO. Formal analysis: KRB, KF. Investigation: KRB, DAP, LMO. Resources: JDC, TR, KF, KW, JFC, AP, AMG. Data curation: KRB. Writing—original draft: KRB. Writing—review and editing: KRB, DAP, LMO, KF, KW, JDC, JFC, AP, AMG. Visualization: KRB. Supervision: AMG. Funding acquisition: KRB, JFC, AMG.

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Correspondence to Alison M. Goate.

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Conflict of interests

AMG: Scientific advisory board (SAB) for Denali Therapeutics (2015-2018), SAB for Pfizer (2019), SAB for Genentech, consultant for GSK, AbbVie, Biogen and Eisai. All other authors declare no competing interests.

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Bowles, K.R., Pugh, D.A., Oja, LM. et al. Dysregulated coordination of MAPT exon 2 and exon 10 splicing underlies different tau pathologies in PSP and AD. Acta Neuropathol 143, 225–243 (2022). https://doi.org/10.1007/s00401-021-02392-2

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