@article{ca4a14e701cf4db88518aa25b1c880f3,
title = "Dysregulation of RNA Splicing in Tauopathies",
abstract = "Pathological aggregation of RNA binding proteins (RBPs) is associated with dysregulation of RNA splicing in PS19 P301S tau transgenic mice and in Alzheimer's disease brain tissues. The dysregulated splicing particularly affects genes involved in synaptic transmission. The effects of neuroprotective TIA1 reduction on PS19 mice are also examined. TIA1 reduction reduces disease-linked alternative splicing events for the major synaptic mRNA transcripts examined, suggesting that normalization of RBP functions is associated with the neuroprotection. Use of the NetDecoder informatics algorithm identifies key upstream biological targets, including MYC and EGFR, underlying the transcriptional and splicing changes in the protected compared to tauopathy mice. Pharmacological inhibition of MYC and EGFR activity in neuronal cultures tau recapitulates the neuroprotective effects of TIA1 reduction. These results demonstrate that dysfunction of RBPs and RNA splicing processes are major elements of the pathophysiology of tauopathies, as well as potential therapeutic targets for tauopathies.",
keywords = "EGFR, MYC, NetDecoder, RNA metabolism, RNA splicing, RNA-seq, TIA1, neuroprotection, stress granule, tauopathy, transcriptome",
author = "Apicco, {Daniel J.} and Cheng Zhang and Brandon Maziuk and Lulu Jiang and Ballance, {Heather I.} and Samantha Boudeau and Choong Ung and Hu Li and Benjamin Wolozin",
note = "Funding Information: We gratefully acknowledge receiving brain tissues from the Boston University ADC Brain Bank (AG013846) and the Harvard Brain Tissue Resource Center. Funding was provided by the following agencies and foundations: for B.W. NIH-NIEHS (ES020395), NINDS (NS089544), NIA (AG050471, AG056318, and AG061706), the Alzheimer Association, BrightFocus Foundation, and the CureAlzheimer Foundation; and for H.L. NIH (CA196631 and AG056318), the Glenn Foundation for Medical Research, the Mayo Clinic Center for Biomedical Discovery, the Mayo Clinic Cancer Center, and the Margaret T. Grohne Cancer Immunology and Immunotherapy Program. D.J.A. and C.Z. designed, performed, and analyzed experiments and helped to write and edit the manuscript; B.M. and L.J. designed and performed experiments; S.B. performed experiments; H.I.B. and C.U. contributed to experimental analysis; and H.L. and B.W. conceived of the project, designed experiments, analyzed experiments, and helped to write and edit the manuscript. B.W. is co-founder and chief scientific officer of Aquinnah Pharmaceuticals Inc. D.J.A. is now an employee of Biogen Inc. The other authors declare no competing interests. Funding Information: We gratefully acknowledge receiving brain tissues from the Boston University ADC Brain Bank ( AG013846 ) and the Harvard Brain Tissue Resource Center . Funding was provided by the following agencies and foundations: for B.W., NIH-NIEHS ( ES020395 ), NINDS ( NS089544 ), NIA ( AG050471 , AG056318 , and AG061706 ), the Alzheimer Association , BrightFocus Foundation , and the CureAlzheimer Foundation ; and for H.L., NIH ( CA196631 and AG056318 ), the Glenn Foundation for Medical Research , the Mayo Clinic Center for Biomedical Discovery , the Mayo Clinic Cancer Center , and the Margaret T. Grohne Cancer Immunology and Immunotherapy Program . Publisher Copyright: {\textcopyright} 2019 The Authors",
year = "2019",
month = dec,
day = "24",
doi = "10.1016/j.celrep.2019.11.093",
language = "English (US)",
volume = "29",
pages = "4377--4388.e4",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "13",
}